MEN2 Database

A significant database revision occurred in April 2022 (manuscript submitted).

Updates were made to the RET variant Classification methods and the MEN2 Phenotype descriptions.

Reference sequences were GRCh37 and NM_020975.6. cDNA number 1 is the ‘A’ of the start codon. Click any Column Header to sort the display. ‘Live Search’ any term in the search box, such as ‘exon 10’, ‘benign’, etc...

Click on the ‘Comments’ column icon for additional information.

Click for a detailed description of: Abbreviations, Classification, MEN2 Phenotype, MTC Onset, See Comments.

171 variants found

Genomic Position	Location	Genotype	Protein Change	Classification	MEN2 Phenotype	MTC Onset	References
1	43595999	Exon 2	c.166C>A	p.L56M	likely benign	No MEN2 Disease		▶ First report, individual with HSCR: no MEN2 listed (PMID 1079020). Second report, individual with PHEO and MTC at 62 yr. Third report, individual with unilateral MTC at 58 yr (PMID 30072953). GnomAD frequency 0.27% (0.48% European cohort), very common for an uncommon disease.
5	43601830	Exon 5	c.874G>A see comments	p.V292M	Uncertain	Unknown	44	▶ First report, family had 1 with the variant genotype: unilateral MTC and unilateral PHEO at 44 yr. Second report, p.V292M was found in the germline of a 45 yr old colorectal cancer patient: No mention of MEN2 screening (PMID 17344846). Functional studies: RET activation (PMID 20039896). GnomAD frequency 0.06% (0.7% East Asian cohort), very common for an uncommon disease. In addition (PMID 21655256), p.V292M/R67H/R982C allele was found in trans with p.C634Y in a Chinese family, genotype c.[1901G>A];[200G>A;874G>A;2944C>T]. Note, variants p.R67H and p.R982C are common and likely benign. One family member had both variant RET alleles and MTC onset at 13 yrs. Family members with p.C634Y only had MEN2A. Family members with the p.V292M/R67H/R982C allele only had MTC (70 yr) and C-cell hyperplasia (44 yr).
8	43601840	Exon 5	c.884C>T	p.T295M	Uncertain	Unknown	49	▶ First report, French individual with MTC at 49 yr (PMID 28946813). Second report, individual with unilateral PHEO at 44 yr (PMID 30877234).
10	43601917	Exon 5	c.961G>A	p.G321R	Uncertain	Unknown	61	▶ Czech family had 4 with the variant genotype: 1 had metastatic MTC (61 yr), and 1 had bi-lateral C-cell hyperplasia at 42 yr (PMID 16419493).
11	43601969	Exon 5	c.1013C>T	p.T338I	Uncertain	Unknown		▶ First report, individual with HSCR (PMID 11955539). Second report, individual with MTC (PMID 21054478). Third report, family had 2 with variant genotype: 1 had MTC only (PMID 21810974). Additional references: PMID 20516206 and 31510104. Functional studies: PMID 21810974 and 25440022
14	43606904	Exon 7	c.1513_1518del GAGGGG	p.E505_G506del	Pathogenic	Classical MEN2A	37	▶ Family had 1 with the de novo inframe deletion variant: MTC at 37 yr and bilateral PHEO at 31 yr (PMID 26765577). Genotype was c.1512_1517delGGAGGG in the reference. Functional studies: RET activation (PMID 26765577).
16	43607553	Exon 8	c.1529C>T	p.A510V	Uncertain	Unknown	55	▶ First report, French individual with MTC only at 55 yr (PMID 20103606). Second report, two unrelated French individuals: 1 had MTC at 69 yr (PMID 28946813). Functional studies: RET activation (PMID 20103606).
18	43607555	Exon 8	c.1531G>A	p.E511K	Uncertain	Unknown	38	▶ First report, French individual with MTC only at 66 yr (PMID 20103606). Second report, Portuguese family had 4 with the variant: 1 had MTC (65 yr), and 3 were asymptomatic (49, 51, and 56 yr). Third report, two unrelated French individuals: 38 yr and 73 yr with MTC (PMID 28946813). Functional studies: RET activation (PMID 20103606 and 21551259).
20	43607563	Exon 8	c.1539G>A	p.A513=	Likely Benign	No MEN2 Disease		▶ Individual with MTC (60 yr); and synonymous variant was described as likely benign (PMID 28946813).
22	43607568	Exon 8	c.1544_1545 delGCinsCT	p.C515S	Likely Pathogenic	Unclassified MEN2	35	▶ Italian family had 2 with the variant genotype: 1 had multifocal MTC at 35 yr, 1 had bilateral MTC at 58 yr (PMID 18631007). Functional studies: RET activation (PMID 18631007).
24	43607568	Exon 8	c.1544G>T	p.C515F	Uncertain	Unknown	49	▶ French individual with MTC only (49 yr); and described as likely pathogenic (PMID 28946813).
26	43607569	Exon 8	c.1545C>G see comments	p.C515W	Likely Pathogenic	Unknown	60	▶ Family had 9 with the variant genotype, of which 1 was homozygous (PMID 25725622). The homozygous individual had hemithyroidectomy at 27 yr, then complete thyroidectomy with identified MTC at 60 yr. One heterozygous individual had unilateral MTC at 63 yr, while the other 7 heterozygous individuals had no symptoms or surgery. Functional studies: RET activation (PMID 25725622).
28	43607597	Exon 8	c.1573C>T see comments	p.R525W	Uncertain	Unknown		▶ First report, p.R525W was found in one Brazilian individual in a cancer-free control cohort; individual/clinical information was unavailable (PMID 25425582). Second report, family had 2 with the variant genotype: both no surgery and no symptoms at 30 yr and 32 yr (PMID 26356818). In this family, p.R525W was also found in trans with p.S891A in two family members, genotype c.[1573C>T ];[ 2671T>G]: both had MTC (58 yr and 65 yr).
32	43607610	Exon 8	c.1586_1594dup AGGAGTGTG	p.Glu529_Cys531dupEEC	likely pathogenic	FMTC	19	▶ Family had 4 with the variant genotype: 4 had MTC (PMID 10323403). Individuals may also have corneal nerve thickening.
34	43607615	Exon 8	c.1591T>C	p.C531R	Uncertain	Unknown	53	▶ First report, French individual with MTC only at 53 yr (PMID 20103606). Second report, two unrelated French individuals: 58 yr and 59 yr with MTC (PMID 28946813). Third report, individual with PHEO only (48 yr, PMID 30877234). Fourth report, Portuguese family had 2 with the variant genotype: 1 had MTC (64 yr), 2 had bi-lateral PHEOs (44 and 53 yr, 50 and 64 yr); PMID 27838608. Functional studies: RET activation (PMID 20103606).
36	43607621	Exon 8	c.1597G>A	p.G533S	Uncertain	Unknown		▶ First report, variant found in a Thai sporadic HSCR patient; not screened for MEN2 (PMID 17009072). Patient also had Down syndrome (2-10% have HSCR). Second report, Chinese individual with HSCR (PMID 23084198). Third report, individual had a paraganglioma or PHEO (PMID 22517557).
38	43607621	Exon 8	c.1597G>T see comments	p.G533C	Pathogenic	Classical MEN2A; or FMTC	21	▶ Youngest with MTC: metastatic MTC at 21 yr (PMID 14602786). Youngest with PHEO: 29 yr (PMID 23461807). Greek and Spanish/Brazil family reports. One individual was homozygous for p.G533C and had metastatic MTC at 26 yr (PMID 16649977). French individual with PHEO at 76 yr (PMID 30877234). p.G533C may have variable penetrance; and specific RET polymorphisms may modify phenotype (PMID 19138318). Functional studies: RET activation (PMID 21834681). Additional references: PMID 23745650, 21834681, 18805915, and 17704047.
40	43607645	Exon 8	c.1621T>C	p.C541R	Uncertain	Unknown		▶ Suspicion of MEN2B and HSCR before 1 year of age, but further clinical information was unavailable (PMID 28946813). Asymptomatic parents were not tested for variant. Described as likely pathogenic.
42	43607666	Exon 8	c.1642G>A	p.G548S	Uncertain	Unknown	53	▶ Two unrelated French individuals: 1 had MTC only (53 yr), 1 with MTC and PHEO (53 yr). Described as Variant of Uncertain Significance (PMID 28946813).
44	43608301	Exon 9	c.1649G>A	p.G550E	Uncertain	Unknown	32	▶ Family has 3 with the variant genotype: 1 had MTC (32 yr), 2 were asymptomatic (PMID 22648435).
46	43608992	Intron 9	c.1760-12G>A		Benign	No MEN2 Disease		▶ Individual with metastatic MTC at 68 yr (PMID 15858153). Reference called sequence change, IVS9-11G>A, using RET GenBank sequence AJ243297.
48	43609043	Exon 10	c.1799G>A	p.R600Q	Uncertain	Unknown	46	▶ First report, Spanish family had 6 with the variant genotype: 1 had MTC (46 yr), 4 were asymptomatic (52, 50, 45, 19 yr), and 73 yr old was not screened (PMID 10612852). Genotype is listed as c.1730G>A in reference. Second report, Chinese individual with MTC at 41 yr (PMID 33827484).
50	43609051	Exon 10	c.1807A>C see comments	p.K603Q	Likely Pathogenic	Unknown	35	▶ First report, Caucasian family had 3 with the variant genotype: 1 had metastatic MTC (35 yr), 2 had micropapillary carcinoma (PMID 11746981). Second report, French individual had p.K603Q and p.L790F, genotype c.[1807A>C(;)2370G>T]: MTC (60 yr). Unknown if sequence changes are in cis or trans (PMID 28946813). Functional studies: RET activation (PMID 15277225).
54	43609061	Exon 10	c.1817A>G	p.Y606C	Uncertain see comments	Unknown		▶ First report, family had 2 with the variant genotype: 1 MTC (PMID 15858153). Second report: Individual with bilateral/multifocal MTC at 58 yr (PMID 18248647). Third report, Chinese family had 6 with c (exact genotype not given): 3 MTC, range 47 to 53 yr (PMID 26254625). Functional studies: RET activation (PMID 18248647). Note, although the p.Y606C classification is Uncertain, if the c.1817A>G genotype can be confirmed for the p.Y606C variant in PMID 26254625, classification would be Likely Pathogenic.
56	43609069	Exon 10	c.1825T>A	p.C609S	Pathogenic	Unknown		▶ German individual: HSCR only, thyroid was normal at 30 yr. No MEN2 symptoms reported. Additional reference: PMID 15326638.
58	43609069	Exon 10	c.1825T>C	p.C609R	Pathogenic	Classical MEN2A; or MEN2A with HSCR	27	▶ Youngest with MTC: 27 yr (PMID 17895320). Youngest with PHEO: 22 yr (PMID 15771139). Individuals may also have HSCR (PMID 10982477, 17895320 and 17188172). Functional studies: RET activation (PMID 9879991, 17102091). Additional references: PMID 20979234, 14561794 and 16707008.
60	43609069	Exon 10	c.1825T>G	p.C609G	Pathogenic	Classical MEN2A	4	▶ Youngest with MTC: 4 yr (PMID 20979234). Three family reports, 6 have the variant: 5 MTC and 4 PHEO (PMID 20979234). Additional references: PMID 12037758, 18063059 and 15326638.
62	43609070	Exon 10	c.1826G>A	p.C609Y	Pathogenic	Classical MEN2A; MEN2A with HSCR; or FMTC	14	▶ Youngest with MTC: 14 yr (PMID 15531714). Youngest with PHEO: 25 yr (PMID 27994876). Youngest with HPT: 38 yr (PMID 8855832). One large multi-generation FMTC family, PMID 10462620. Individuals may also have HSCR (PMID 7633441, 9384613, 9498388, 20979234, 15531714, and 17021738) or corneal nerve thickening (PMID 12686527). Functional studies: PMID 9230192. Additional references: PMID 19472011 and 18063059. Has been found with another RET change, see c.1846_1848delGAG.
64	43609070	Exon 10	c.1826G>C	p.C609S	Pathogenic	Classical MEN2A	15	▶ Youngest with MTC: 15 yr (PMID 20979234). Youngest with PHEO: 19 yr (PMID 19475497). Two family reports, 18 have the variant: 14 had MTC, 4 had PHEO, and 2 had HPT (PMID 20979234). Functional studies: RET activation (PMID 16343103). Additional references: PMID 11524247, 12050290, 18976013 and 15452453.
66	43609070	Exon 10	c.1826G>T	p.C609F	Pathogenic	Classical MEN2A	18	▶ Youngest with MTC: 18yr; and youngest with PHEO: 33yr (PMID 22734615). Two family reports with MTC and PHEO (PMID 20979234). Additional reference: PMID 18058472
68	43609071	Exon 10	c.1827C>G	p.C609W	Pathogenic	Unknown		▶ This variant has been reported to cause HSCR (PMID 7581377, 7881414, and 11694544). Functional studies: RET activation (PMID 9502784 and 9230192).
70	43609071	Exon 10	c.1827C>T	p.C609=	Likely Benign	No MEN2 Disease		▶ Polish family had 3 with the variant: one had monofocal MTC (10 yr), 2 were asymptomatic (34 yr and 7 yr).
72	43609075	Exon 10	c.1831T>A	p.C611S	Likely Pathogenic	Unknown		▶ Reported as causative of MEN2 in diagnostic methods manuscripts, no patient/clinical information (PMID 8807338 and 14718397).
74	43609075	Exon 10	c.1831T>C	p.C611R	Likely Pathogenic	Unknown	30	▶ First report, individual with bilateral PHEO at 57 yr (PMID 19029228). Second report, individual with MTC at 30 yr and p.C611R (exact genotype not given, PMID 30624503). Third report, individual with MTC at 53 yr, PHEO, and p.C611R (exact genotype not given, PMID 28018431). Individuals may also have HSCR (PMID 11694544). Functional studies: RET activation (17102091)
76	43609075	Exon 10	c.1831T>G	p.C611G	Pathogenic	Unclassified MEN2	28	▶ First report, Spanish family had 4 with the variant: 3 had MTC (28 yr old had metastatic MTC), 1 had C-cell hyperplasia (PMID 9677065). Has also been described as causing FMTC (PMID 11073534) or associated with HSCR (PMID 34092334).
78	43609076	Exon 10	c.1832G>A	p.C611Y	Pathogenic	Classical MEN2A; or MEN2A with CLA	6	▶ Youngest with MTC: 6 yr (PMID 20063095). Youngest with PHEO: 19 yr (PMID 33362715). Youngest with HPT: 40 yr (PMID 8855832). Patients may also have CLA (PMID 30300539). Functional studies: PMID 9230192. Additional references: PMID 20979234, 25379023, 10951350, and 18062802.
80	43609076	Exon 10	c.1832_1833 delGCinsAT	p.C611Y	Pathogenic	Unclassified MEN2	55	▶ Family had 5 with the variant genotype: 4 had MTC (55 yr old had metastatic MTC). Two other family members, not genotyped, had thyroid carcinoma and an adrenal tumor. Reference article is in German (PMID 18302097).
82	43609076	Exon 10	c.1832G>C	p.C611S	Likely Pathogenic	Unknown		▶ Reported as causative of MEN2 in diagnostic methods manuscript, no patient/clinical information (PMID 14718397).
84	43609076	Exon 10	c.1832_1833 delGCinsCT	p.C611S	Likely Pathogenic	Unclassified MEN2	47	▶ Japanese family had 3 with the variant genotype: 2 had MTC, 1had a suspected PHEO, 1 had HSCR. Additional reference: PMID 19318731.
86	43609076	Exon 10	c.1832G>T	p.C611F	Pathogenic	Classical MEN2A; or FMTC	14	▶ Youngest for MTC at 14 yr (PMID 22584715, p.C611F [exact genotype not given]). FMTC phenotype was common (PMID 22584715, 20979234 and 11331212); one case of PHEO at 58 yr (PMID 19258401). Additional reference: PMID 11230481.
88	43609076	Exon 10	c.1832_1833 delGCinsTT	p.C611F	Pathogenic	Unclassified MEN2	36	▶ First report, Spanish family had 4 with the variant genotype: 3 had MTC (PMID 20979234). Second report, 32 yr old Chinese individual with PHEO and HPT (PMID 33827484). Additional reference: PMID 20979234
90	43609077	Exon 10	c.1833C>G	p.C611W	Pathogenic	Classical MEN2A	14	▶ Two families had 5 with variant: 5 had MTC (youngest 14 yr), 1 had PHEO (PMID 20979234). Functional studies: PMID 9230192. Additional references: PMID 20979234, 14739494, 11502806, and 7916559.
92	43609090	Exon 10	c.1846G>C	p.E616Q	Uncertain	Unknown		▶ Family had 3 with the variant: 1 had unilateral PHEO (42 yr) with bilateral C-cell hyperplasia (43yr), 1 had HSCR, and 1 was unaffected. Functional studies: RET activation (PMID 27704398).
94	43609090	Exon 10	c.1846_1848delGAG see comments	p.E616del	Uncertain	Unknown		▶ Family had 3 with the variant: all asymptomatic. In this family, p.E616del was also found in trans with p.C609Y in two individuals, genotype c.[1826G>A];[1846_1848delGAG]: 2 had MTC.
98	43609096	Exon 10	c.1852T>A	p.C618S	Pathogenic	Classical MEN2A; MEN2A with HSCR; or FMTC	9	▶ Youngest with MTC: 9 yr; and youngest with PHEO: 29 yr (PMID 9498388). Individuals may also have HSCR (PMID 9384613, 9498388 and 7716719). Additional references: PMID 22068382, 20979234, 20119574, and 18062802. Has been found with another RET change, see p.E623K.
100	43609096	Exon 10	c.1852T>C	p.C618R	Pathogenic	Classical MEN2A; MEN2A with HSCR; or FMTC	8	▶ Youngest with MTC: 8 yr (PMID 11935126). Youngest with PHEO: 19 yr (PMID 18063059). Patients may also have HSCR, which occurs in ~33% of p.C618R families (PMID 7881414, 8675603 and 9259198). Functional studies: RET activation (PMID 17102091, 9879991 and 9230192). Additional references: PMID 17895320 and 20979234.
102	43609096	Exon 10	c.1852T>G	p.C618G	Pathogenic	Classical MEN2A; or FMTC	9	▶ Youngest with MTC: 9 yr (PMID 16325365). Youngest with PHEO: 22 yr (PMID 18062802). Functional studies: PMID 9230192. Additional references: PMID 8640806, 18063059, and 20979234.
104	43609097	Exon 10	c.1853G>A	p.C618Y	Pathogenic	Classical MEN2A; or FMTC	25	▶ Youngest for MTC: 25 yr (PMID 20979234). Report of FMTC (PMID 33827484). Three family reports, 6 have the variant genotype: 6 had MTC, 1 had PHEO (PMID 20979234). Functional studies: PMID 9230192. Additional references: PMID 9699127, 7608256, and 11230481. Has been found with another RET change, see p.D631=.
106	43609097	Exon 10	c.1853G>C	p.C618S	Pathogenic	Classical MEN2A; MEN2A with HSCR	8	▶ Average age for youngest MTC, 8 yrs (PMID 29656518). Seven family reports, 14 have the variant genotype: 12 had MTC, 2 had PHEO (PMID 20979234). Individuals may also have HSCR (PMID 9498388 and 9384613). Additional references: PMID 8625130, 9003111, 20979234, and 15164440. Has been found with another RET change, see p.S891=.
108	43609097	Exon 10	c.1853G>T	p.C618F	Pathogenic	Classical MEN2A; or FMTC	5	▶ Youngest with PHEO: 32 yr (PMID 19258401). Four family reports, 27 have the variant: 21 had MTC (youngest 5 yr), 2 had PHEO, 2 had HPT (PMID 20979234). Functional studies: RET activation (PMID 29625052). Additional references: PMID 9839497, 18063059, and 7670926.
110	43609098	Exon 10	c.1854C>G	p.C618W	Likely Pathogenic	Unknown		▶ Individual report, no patient/clinical information (PMID 28946813). Reported as novel MEN2 causative variant in a diagnostic methods manuscript, no patient/clinical information (PMID 14718397).
112	43609101	Exon 10	c.1857_1858delCTinsTC see comments	p.C620R	Pathogenic	MEN2A with HSCR	28	▶ Dutch family had 4 with indel variant: 1 had MTC with PHEO (at 28 yr), 1 had HSCR (3 yr), 1 had suspected MEN2A, 1 normal thyroidectomy (at 5yr). Genotype c.1857_1858delinsTC results in a synonymous variant at codon 619 and a missense change at 620 (p.C620R). Additional reference: PMID 9824583.
114	43609102	Exon 10	c.1858T>A	p.C620S	Pathogenic	Unknown	38	▶ First report, individual with MTC at 38 yr (PMID 11238493). Second report, individual with a family history of MEN2A (PMID 7849720). Additional references: PMID 18062802 and 14718397.
116	43609102	Exon 10	c.1858T>C	p.C620R	Pathogenic	Classical MEN2A; MEN2A with HSCR; or FMTC	6	▶ Youngest with MTC: 6 yr (PMID 20979234 and 12711285). Youngest with PHEO: 19 yr (PMID 18063059). Individuals may also have HSCR (PMID 33754314, 17021738, 8909322, 11955539, 8918855, 7881414, and 17188172). Functional studies: RET activation (PMID 14715928, 9879991, 17102091 and 9230192). FMTC references: PMID 20152359 and 17316110.
118	43609102	Exon 10	c.1858T>G	p.C620G	Pathogenic	Classical MEN2A; or MEN2A with HSCR	22	▶ Report of three families where 13 have the variant: 7 had MTC (youngest 22 yr), 1 had PHEO, 4 had HSCR (PMID 20979234). Additional references: PMID 9223675, 11073534, and 11502806.
120	43609103	Exon 10	c.1859G>A	p.C620Y	Pathogenic	Classical MEN2A; MEN2A with HSCR; or FMTC	18	▶ Youngest with MTC: 18 yr (PMID 16868135 and 20979234). Youngest with PHEO: 36 yr (PMID 18063059). Seven family reports, 19 have the variant: 14 had MTC, 1 had HSCR (PMID 20979234). FMTC reference: PMID 8797874. Individual with HSCR (PMID 20979234). Functional studies: RET activation (PMID 8654369, 9230192, and 18248647). Additional references: PMID 9820617.
122	43609103	Exon 10	c.1859G>C	p.C620S	Pathogenic	Classical MEN2A; MEN2A with HSCR; or FMTC	14	▶ Four family reports: 14 had MTC (youngest 14 yr), 3 had PHEO (PMID 20979234). Individuals may also have HSCR (PMID 9681852, 9745455 and 10549772) or HPT (PMID 9745455). FMTC (with HSCR) reference: PMID 24805091. Additional references: PMID 18062802 and 14517954.
124	43609103	Exon 10	c.1859G>T	p.C620F	Pathogenic	Classical MEN2A; or Unclassified MEN2	27	▶ Youngest with PHEO: 30 yr (PMID 16705552). Three family reports, 8 have the variant genotype: 3 had MTC (youngest 27 yr), 2 had PHEO (PMID 20979234). Czech family report: 58yr with metastatic MTC (PMID 16705552). Additional references: PMID 7916559, 8909322, 18976013, 19443294, 18063059 and 7874109.
128	43609103	Exon 10	c.1859_1860delGCinsTG	p.C620L	Likely Pathogenic see comments	Unknown	19	▶ Individual with de novo indel variant: MTC at 19 yr. Note, codon 620 is a highly conserved RET cysteine residue, where a change to any other amino acid is pathogenic. This evidence was used to upgrade this variant from Uncertain to Likely Pathogenic classification, since this indel variant resulted in a change from Cysteine to Leucine.
130	43609104	Exon 10	c.1860C>G	p.C620W	Pathogenic	Unknown	37	▶ Youngest with MTC: 37 yr (PMID 17270543). Family had 2 with the variant: 1 had MTC (PMID 20979234). Individuals may also have HSCR (PMID 9384613). Additional references: PMID 20152359.
132	43609104	Exon 10	c.1860C>T	p.C620=	Likely Benign	No MEN2 Disease		▶ French individual with MTC and PHEO at 70 yr; and variant described as likely benign (PMID 28946813).
134	43609111	Exon 10	c.1867G>A see comments	p.E623K	Uncertain	Unknown		▶ First report, individual described as having inherited MTC (no patient/clinical information, PMID 9068588); and p.E623K was called a rare silent polymorphism. Second report, family had 3 with the variant: asymptomatic at 22, 45, and 78 yr (PMID 15858153). In this family, p.E623K was also found in trans with p.C618S, genotype c.[1852T>A];[1867G>A], in one asymptomatic individual at 17yr.
138	43609127	Intron 10	c.1879+4A>G		Uncertain	Unknown	55	▶ Individual with thyroid cancer at 55 yr: potential MTC (PMID 15579915); and variant previously called IVS10+4G.
140	43609936	Exon 11	c.1888T>C	p.C630R	Pathogenic	Classical MEN2A; or FMTC	1	▶ Youngest with MTC: 1 yr (PMID 15523405). Youngest individual with HPT: 32 yr (PMID 15523405). Family report with at least three affected family members: 63 yr old was diagnosed with MEN2A and had surgery for MTC, PHEO, and hyperparathyroidism (PMID 34777782). FMTC reference: PMID 16053382. Functional studies: RET activation (PMID 9879991). Additional references: PMID 14561794 and 30763276.
142	43609937	Exon 11	c.1889G>A	p.C630Y	Pathogenic	Classical MEN2A; or Unclassified MEN2	22	▶ Youngest with MTC: 22 yr (17895320). First family report: 2 MTC (PMID 9223675). Second family report: 2 had MTC, had 1 HPT at 67 yr (PMID 17527003). Functional studies: RET activation (PMID 34905813 and 10049754).
144	43609937	Exon 11	c.1889G>C	p.C630S	Pathogenic	Unclassified MEN2	39	▶ Japanese individual with multifocal/bilateral MTC at 39 yr (PMID 9223675).
145	43609937	Exon 11	c.1889G>T	p.C630F	Likely Pathogenic	Unknown		▶ Individual with MTC only (PMID 8625130). Has also been described as causing FMTC (PMID 11073534). Functional studies: PMID 9230192.
146	43609938	Exon 11	c.1890C>T see comments	p.C630=	Likely Benign	No MEN2 disease		▶ Individual with MTC at 29 yr. In this individual, the germline p.C630= was found in cis with somatic variant p.C634R (c.1900T>C) in the MTC tissue. Functional studies indicated the presence of the synonymous variant increased RET expression (PMID 30321177).
148	43609939	Exon 11	c.1891G>A	p.D631N	Uncertain	Unknown	59	▶ Family report, 3 with variant: 1 had MTC at 59 yr (PMID 30927507). Functional studies: PMID 10049754.
150	43609939	Exon 11	c.1891G>T	p.D631Y	Pathogenic	Classical MEN2A	30	▶ Youngest with MTC: 30 yr (PMID 16839264). Youngest with PHEO: 19 yr at onset of PHEO symptoms (PMID 33362715). First report, two Korean families had 10 with the variant: 2 had MTC, 4 had PHEO (PMID 16839264; only exons 10 - 11 were sequenced). Second report, family had 7 with variant genotype: 1 had C-cell hyperplasia, 1 had MTC, 3 had PHEO, 1 had HPT (PMID 22274720). Third report, Korean individual with PHEO only at 71 yr (PMID 24134185). Fourth report, French individual with MTC and PHEO at 31 yr (PMID 28946813). Fifth report, Caucasian individual has three sequence changes: p.D631Y, p.S819I, and p.E843D (genotype c.[1891G>T(;)2456G>T(;)2529G>T]): metastatic MTC at 40 yr. Unknown if sequence changes are in cis or trans (PMID 11149622). Additional references: PMIDs 34267909 and 34905813. Functional studies (PMID 34905813 and 10049754).
156	43609940	Exon 11	c.1892A>C	p.D631A	Uncertain	Unknown		▶ Functional studies only, no known families with this sequence change (PMID 10049754).
158	43609940	Exon 11	c.1892A>G	p.D631G	Uncertain	Unknown		▶ First report, p.D631G was found as a somatic variant in a Japanese sporadic MTC patient (PMID 9621513). Second report, Chinese individual with pelvic paraganglioma at 32 yr; described variant as likely pathogenic (PMID 33362715). Functional studies: PMID 10049754.
160	43609940	Exon 11	c.1892A>T see comments	p.D631V	Uncertain	Unknown		▶ p.D631V was found in one individual in a Japanese cohort with PHEOs; individual/clinical information was unavailable (PMID 34439168). Reported as causative of MEN2 in diagnostic methods manuscript, no patient/clinical information (PMID 14718397). Family report, p.D631V was found in cis with p.H665Q in 4 family members, genotype c.[1892A>T;1995C>G]: 2 had PHEO only, 2 were asymptomatic (PMID 15858153).
163	43609941	Exon 11	c.1893C>A see comments	p.D631E	Uncertain	Unknown		▶ No reports of p.D631E alone. Two reports: p.D631E was found with p.C634Y, genotype c.[1893C>A(;)1901G>A]; unknown if in cis or trans (PMID 14718397 and 15858153).
166	43609941	Exon 11	c.1893C>T see comments	p.D631=	Likely Benign	No MEN2 Disease		▶ First report, p.D631= found in a 53 yr old lung cancer patient, no mention of MEN2 screening (PMID 17344846). Second report, individual with MTC (PMID 31510104). Third report, individual had p.D631= with p.C618Y, genotype c.[1853G>A(;)1893C>T]: no patient/clinical information. Unknown if in cis or trans (PMID 14718397).
170	43609941	Exon 11	c.1893_1895del CGA	p.D631del	Likely Pathogenic	Classical MEN2A	31	▶ Chinese family report had 5 with the variant genotype: 4 had PHEO, 3 had MTC, and 1 was asymptomatic at 10yr. Youngest with MTC or PHEO: 31 yr. Deletion of 3 bp essentially causes loss of codon 631. Reference article in Chinese (PMID 17923033); in English: PMID 18845906.
172	43609942	Exon 11	c.1894G>A	p.E632K	Uncertain	Unknown	53	▶ First report, German individual with multifocal MTC at 53 yr (PMID 17605401). Second report, Italian individual with MTC (PMID 31510104 and 25440022). Third report, individual with HSCR (PMID 22648184).
174	43609943	Exon 11	c.1895A>G	p.E632G	Uncertain	Unknown		▶ Caucasian individual with unilateral PHEO at 42 yr, no evidence of MTC (PMID 26497911).
176	43609944	Exon 11	c.1896_1900delinsCGTGC see comments	p.E632_C634delinsDVR	Pathogenic	Unknown		▶ This indel variant changes three amino acids (ELC>DVR) which includes the p.C634R variation (PMID 8099202). Functional studies: RET activation (PMID 8612479). In the oldest reference, codon 634 was called codon 380. Additional reference: PMID 7595167.
178	43609948	Exon 11	c.1900T>A	p.C634S	Pathogenic	Classical MEN2A; or Unclassified MEN2	8	▶ Youngest with MTC: 8 yr (PMID 19675075). Youngest with PHEO: 39 yr (PMID 33362715). Three family reports: 7 had MTC, 5 had PHEO, 1 had HPT (PMID 11524247). Additional references: PMID 18058472, 15531714, and 7874109.
180	43609948	Exon 11	c.1900T>C	p.C634R	Pathogenic	Classical MEN2A; MEN2A with CLA; or FMTC	1.4	▶ Youngest with MTC 17 months (PMID 11900218); PHEO 15 yr (PMID 18063059); and HPT 5 yr (PMID 21449769). Only one family reported as FMTC (PMID 9950371). Individuals may also have cutaneous lichen amyloidosis (PMID 12864791 and 7874109). Functional studies: RET activation (PMID 9879991, 15277225, 7824936, and 9242375). Additional references: PMID 7595171, 7915822, 18062802 and 18976013. Has been found with other RET changes, see p.A640G, p.V648I, p.M700L, and c.1896_1900delinsCGTGC.
182	43609948	Exon 11	c.1900T>G	p.C634G	Pathogenic	Classical MEN2A; or MEN2A with CLA	3	▶ Youngest with MTC: 3 yr (PMID 20223015). Youngest with PHEO: 20 yr at onset of PHEO symptoms (PMID 33362715). Individuals may also have cutaneous lichen amyloidosis (PMID 9111993 and 33827484). Additional references: PMID 12150334, 18062802, 19258401 and 18063059.
186	43609949	Exon 11	c.1901G>A	p.C634Y	Pathogenic	Classical MEN2A; or MEN2A with CLA	0.8	▶ Youngest with MTC 10 months (PMID 19240193); PHEO 8 yr (PMID 23868299); and HPT 10 yr (PMID 9820617). Individuals may also have cutaneous lichen amyloidosis (PMID 17188172, 7491519, 9820617, 12864791, and 7914213). Functional studies: RET activation (PMID 8654369, 9230192, and 7824936). Additional references: PMID 11524247, 18063059, and 20080836. Has been found with other RET changes; see p.D631E, p.D707E, p.I852M.
190	43609949	Exon 11	c.1901G>C	p.C634S	Pathogenic	Classical MEN2A; or FMTC	4	▶ Youngest with MTC: 4 yr (PMID 29656518). Youngest with PHEO: 19 yr (PMID 28099363). FMTC reference: PMID 25143909. Functional studies: RET activation (PMID 15277225). Additional references: PMID 8640806, 18062802, and 7874109. Has been found with another RET change, see p.A641S.
192	43609949	Exon 11	c.1901G>T	p.C634F	Pathogenic	Classical MEN2A; or MEN2A with CLA	3	▶ Youngest with MTC: 3 yr (PMID 29656518). Youngest with PHEO: 26 yr (PMID 25628771). Youngest for HPT: 42 yr (PMID 12604374). Individuals may also have cutaneous lichen amyloidosis (PMID 7874109). Additional references: PMID 16712668, 11900218, 15452453, and 11524247.
194	43609949	Exon 11	c.1901_1902 delinsTG	p.C634L	Likely Pathogenic see comments	Unknown		▶ French individual with PHEO at 37 yr and personal/family history of MTC (PMID 16314641 and 30877234). Note, codon 634 is a highly conserved RET cysteine residue, where a change to any other amino acid is pathogenic. This evidence was used to upgrade this variant from Uncertain to Likely Pathogenic classification, since this indel variant resulted in a change from Cysteine to Leucine.
196	43609950	Exon 11	c.1902C>G	p.C634W	Pathogenic	Classical MEN2A; or MEN2A with CLA	3	▶ Youngest with MTC: 3 yr (PMID 18794325). Youngest with PHEO: 18 yr (PMID 17898100 and 23404858). Youngest with HPT: 5 yr (PMID 27406704). Functional studies: RET activation (PMID 34905813, 7824936 and 8570194). Individuals may also have cutaneous lichen amyloidosis (PMID 11939755). Additional references: PMID 7915822 and 12788868. Has been found with another RET change, see p.R635G.
197	43609940	Exon 11	c.1892_1903dup ACGAGCTGTGCC	p.C634_R635insHELC	likely pathogenic	Classical MEN2A		▶ Family report, 14 have the variant genotype: 12 had MTC, 10 had HPT (PMID 9097963). 12 bp duplication of codons 631-634. Functional studies: PMID 10918602.
198	43609948	Exon 11	c.1900_1908dup TGCCGCACG	p.C634_T636dupCRT	Likely Pathogenic	Classical MEN2A	56	▶ Individual with MTC, PHEO, and HPT at 56 yr (PMID 9452064). 9bp duplication of codons 634-636. Functional studies PMID 10918602.
199	43609951	Exon 11	c.1903C>G see comments	p.R635G	Uncertain	Unknown		▶ No reports of p.R635G alone. p.R635G was found in cis with p.C634W in two MEN2A families and in two MTC patients, genotype c.[1902C>G;1903C>G]: youngest with MTC 4 yr (PMID 12711285). Individuals may also have CLA (PMID 8557249). Additional reference: PMID 7915822.
200	43609951	Exon 11	c.1903C>T	p.R635C	Uncertain	Unknown		▶ Family had 2 with the variant: 1 unilateral PHEO at 41 yr, 1 was asymptomatic at 22 yr (PMID 24449676).
202	43609954	Exon 11	c.1906delins GACCTGTGCCGCC	p.T636delinsDLCRP	Likely Pathogenic	Unclassified MEN2	9	▶ Family had 3 with the variant: 3 had MTC (PMID 15858153). The 1 bp deletion, 13 bp insertion genotype inserts amino acids ELCR after codon 635 along with T636P change. In the reference, c.1906 was called 2101.
204	43609955	Exon 11	c.1907C>T	p.T636M	Uncertain	Unknown	78	▶ Individual with MTC only at 78 yr (PMID 25725622). Functional studies: RET activation (PMID 25725622).
205	43609967	Exon 11	c.1919C>G see comments	p.A640G	Uncertain	Unknown		▶ No reports of p.A640G found alone. p.A640G was found with p.M700L and also with known pathogenic p.C634R variant in an MEN2A patient, genotype c.[1900T>C;1919C>G;2098A>T]: MTC at 26 yr and PHEO (PMID 22500673). Daughter inherited no RET changes, so these three variants are likely in cis. Original report on patient when only p.C634R and p.A640G (c.[1900T>C;1919C>G]) were found: PMID 10522989.
207	43609969	Exon 11	c.1921G>T see comments	p.A641S	Uncertain	Unknown		▶ First report, family with p.Ala641Ser where no MTC developed in individuals even at the age of 60 years (PMID 23067224). Second report, p.A641S was found in cis with p.C634S in a large MEN2A family, genotype c.[1901G>C;1921G>T] (PMID 15592804). Functional studies: PMID 23067224 and 15592804.
210	43609978	Exon 11	c.1930T>G	p.F644V	Uncertain	Unknown	35	▶ French individual with MTC at 35 yr (PMID 28946813).
212	43609990	Exon 11	c.1942G>A see comments	p.V648I	Likely Benign	No MEN2 Disease		▶ First report, family had 2 with variant: 1 had C-cell hyperplasia, 1 was asymptomatic (PMID 21810974). Functional studies: PMID 21810974. Second report, three unrelated French individuals: MTC at 21yr, 65 yr, and 68 yr; and described variant as likely benign (PMID 28946813). Third report, two Italian individuals: 1 had MTC and 1 was unaffected (PMID 31510104). Fourth report, family had 2 with the variant: both asymptomatic (22 and 37 yr, PMID 18209889 and 12466368). In this family, p.V648I was found in trans with p.C634R in one family member, genotype c.[1900T>C];[1942G>A]: MTC at 34 yr. Fifth report, family had 6 with the variant genotype: one had surgery at 52 yr, no MTC (PMID 26247112). In this family, p.V648I was found in trans with p.V804L in one family member, genotype c.[1942G>A];[2410G>C]: MTC at 42 yr.
218	43609994	Exon 11	c.1946C>T see comments	p.S649L	Likely Benign	No MEN2 Disease		▶ PMID 19906784 and 29656518 indicates p.S649L is a rare non-pathogenic polymorphism rather than a disease-causing mutation. Functional studies: lower or equivalent to WT RET activity (PMID 18322301, 21551259, and 23067224). Four unrelated individual reports: 2 had MTC only, 1 had HPT only (24 yr), 1 had elevated calcitonin (47 yr). Fifth individual report, p.S649L was found in trans with p.C634R in a single Polish MEN2A patient, genotype c.[1900T>C];[1946C>T] (PMID 18058472). Family report, 5 have the variant genotype: 1 had MTC only (69 yr). Second family report, 3 have the variant genotype: 2 were asymptomatic (75, 41 yr), 1 had elevated calcitonin (43 yr). Third family report, 4 have the variant genotype: 3 had C-cell hyperplasia (64, 44, 20yr), 1 was asymptomatic (60yr) (PMID 18322301). In this family, p.S649L was found in trans with a de novo p.C634W in one family member, genotype c.[1902C>G];[1946C>T ]: described as MEN2. Additional references: PMID 15320968 and MEN2 meeting poster P20 http://www.hormones.gr/preview.php?c_id=622.
228	43609995	Exon 11	c.1947G>A	p.S649=	Uncertain	Unknown		▶ Three individuals with HSCR; possible splicing variant and may require another locus for HSCR (PMID 10090908 and 10618407). One individual described as having FMTC with p.S649= (genotype not published, PMID 16118333). Functional studies: splicing variation will delete 23 amino acid from RET transmembrane domain (PMID 10618407). Likely benign for MEN2 due to synonymous variant and possible splicing variant predicted to cause a large deletion.
230	43610043	Exon 11	c.1995C>G see comments	p.H665Q	Uncertain	Unknown		▶ No reports of p.H665Q found alone. Family had p.H665Q in cis with p.D631V in 4 family members, genotype c.[1892A>T;1995C>G]: 2 had PHEO only, 2 were asymptomatic (PMID 15858153).
232	43610044	Exon 11	c.1996A>G	p.K666E	Likely pathogenic	Unclassified MEN2	35	▶ First report, family had 8 with variant: 3 had MTC (57 yr, 49 yr, 35 yr), 2 had C-cell hyperplasia (34 yr, 53 yr). Second report, family had 2 with variant: 1 had MTC at 64 yr. Third report, family had 5 with variant: 1 had PHEO at 35 yr (PMID 15858153). Forth report, individual with MTC at 64 yr (PMID 21690267). Functional studies: RET activation (PMID 21690267). Additional reference: PMID 30927507.
234	43610045	Exon 11	c.1997A>C	p.K666T	Likely Pathogenic	Classical MEN2A	41	▶ French individual with MTC and PHEO at 41 yr; and variant described as likely pathogenic (PMID 28946813).
236	43610045	Exon 11	c.1997A>G	p.K666R	Uncertain	Unknown	38	▶ Individual with MTC only at 38 yr (PMID 25319874).
238	43610045	Exon 11	c.1997A>T	p.K666M	Uncertain	Unknown	40	▶ First report, family had 4 with the variant: 3 had C-cell hyperplasia only (16, 41, 45yr), 1 no surgery at 3 yr (PMID 21678021). Four additional family members have both an MEN1 (menin) mutation and the p.K666M RET variant: 2 had MTC (40 yr, 46 yr). Second report, Italian individual described as having the FMTC phenotype (PMID 20516206).
240	43610046	Exon 11	c.1998G>C	p.K666N	Likely pathogenic	Unknown	63	▶ French individual with MTC at 63 yr (PMID 28946813); and variant described as likely pathogenic.
242	43610046	Exon 11	c.1998G>T see comments	p.K666N	Likely pathogenic	Classical MEN2A; or Unclassified MEN2	22	▶ Variant described as likely pathogenic and associated with low disease penetrance. Functional studies: RET activation (PMID 20103606). First report: French individual with MTC only at 65 yr (PMID 20103606). Second report: French individual with MTC only at 59 yr (PMID 28946813). Third report: family had 6 with variant: 2 had MTC (55 yr, 70 yr). Fourth report, 7 unrelated individual cases with variant and MTC at 22, 23, 33, 49, 51, 59, or 64 yr. Two of these individuals had a second RET change c.2608-24G>A (benign) or p.V412M (uncertain). Two cases were multifocal MTC, and all were negative for PHEO and HPT screening (PMID 27673361). Fifth report: single individual with MTC and HPT at 54 yr (link.springer.com/journal/508/126/3/suppl/page/1 abstract P16). Sixth report: family had 5 with variant: 1 had MTC (32 yr), 1 had C-cell hyperplasia (30 yr), and 3 were asymptomatic (25, 43, and 61yr); PMID 29408964. In this family, p.K666N was also found as homozygous in 1 family member genotype c.1998[G>T];[G>T] with MTC and bi-lateral PHEO (58 yr).
246	43610046	Exon 11	c.1998delGins TTCT	p.K666delinsNS	Likely Pathogenic	Classical MEN2A; or Unclassified MEN2	12	▶ Indel mutates codon 666 (p.K666N due to codon sequence change AAG-AAT), then inserts a Serine. A 12 yr old had metastatic MTC (PMID 15844786). French individual with MTC at 58 yr (PMID 28946813). Variant may have low penetrance (MTC penetrance <40%, PHEOs <10%); and report of PHEO at 48 yr (www.endocrine-abstracts.org/ea/0011/ea0011p501.htm). Functional studies: RET activation (PMID 16954442).
248	43610085	Exon 11	c.2037C>T see comments	p.P679=	Benign	No MEN2 Disease		▶ First report, French individual with MTC at 45 yr; and described as likely benign (PMID 28946813). Second report, two Chinese individuals with MTC at 26 and 72 yr; not clear if related or not (PMID 33827484). Third report, Chinese family where p.P679= was found with p.C634R in one MEN2A patient, genotype c.[1900T>C];[2037C>T] (likely in trans): MTC and PHEO. Two family members had p.P679= only and were unaffected (PMID 28569245). GnomAD frequency 0.11% (1.4% East Asian cohort), very common for an uncommon disease.
250	43610100	Exon 11	c.2052G>A	p.P684=	Benign	No MEN2 Disease		▶ French individual with MTC at 75 yr; and this synonymous variant is described as likely benign (PMID 28946813). Listed as c.2052G>A, p.P648P in reference.
252	43610105	Exon 11	c.2057G>A	p.S686N	Uncertain	Unknown		▶ Iranian family with 2 have the variant genotype: 1 MTC and the other had a thyroidectomy due to thyroid nodules at 18yr (PMID 21765987). Only RET exons 10, 11, and 16 were investigated.
254	43610119	Exon 11	c.2071G>A	p.G691S	Benign	No MEN2 Disease		▶ Common polymorphism, not causative of MEN2 disease (GnomAD 21% MAF). Functional studies: equivalent to WT RET activity (PMID 18284634). Additional references: PMID 16118333, 16091499, 18976163, 19269918, 12702567, and 10022819.
256	43610145	Exon 11	c.2097C>T	p.S699=	Likely Benign	No MEN2 Disease		▶ French individual with MTC at 62 yr; and this synonymous variant is described as likely benign (PMID 28946813).
258	43610146	Exon 11	c.2098A>T see comments	p.M700L	Uncertain	Unknown		▶ No reports of p.M700L found alone. p.M700L was found with p.A640G and also with known pathogenic variant p.C634R in an MEN2A patient, genotype c.[1900T>C;1919C>G;2098A>T]: MTC (26 yr) and PHEO (PMID 22500673). Daughter inherited none of these RET changes, so these three variants are likely in cis. In original report, only p.C634R and p.A640G were found: PMID 10522989.
260	43610169	Exon 11	c.2121T>A see comments	p.D707E	Uncertain	unknown	18	▶ Chinese family (PMID 27798940) had 15 with variant: 8 had MTC only (18-50 yr), 5 had MTC and PHEO (26-50yr). Note that 2 family members had MTC and did not have this variant. Second report, Chinese family had p.D707E in cis with p.C634Y in 33 family members, genotype c.[1901G>A;2121T>A].: 11 had MTC (range 14-65 yr), 4 had PHEO (median age 37 yr) (PMID 28943896).
264	43612143	Exon 12	c.2248G>C	p.A750P	Uncertain	Unknown		▶ Two South African individuals in report: described as MEN2A diagnosis, but no patient/clinical information given (PMID 21542403). Variants were detected by scanning 21 RET exons by heteroduplex single-strand conformation polymorphism analysis.
266	43613840	Exon 13	c.2304G>C	p.E768D	Pathogenic	Classical MEN2A; or FMTC	22	▶ FMTC phenotype is more common, only one report of PHEO at 59 yr (PMID 15855933). Functional studies: RET activation (PMID 9242375, 17047083, and 10445857). Additional references: PMID 7784092, 18062802, 9111992 and 15531714.
268	43613840	Exon 13	c.2304G>T see comments	p.E768D	Pathogenic	Unclassified MEN2	41	▶ Three individual reports of MTC only (one bilateral MTC); youngest MTC was 41 yr (PMID 11230481, 12016484, and 12116277). Fourth individual report, p.E768D was found with p.V804M, genotype c.[2304G>T(;)2410G>A] (unknown if in cis or trans): MTC at 25 yr (database submission). Functional studies: RET activation (PMID 14715928, 17047083, and 10445857).
272	43613843	Exon 13	c.2307G>T	p.L769=	Benign	No MEN2 Disease		▶ Common polymorphism, not causative of MEN2 disease. Additional references: PMID 16118333, 15531548, 18976163 and 16091499.
274	43613845	Exon 13	c.2309G>A	p.R770Q	Uncertain	Unknown	42	▶ Family had 3 with the variant: 1 had metastatic MTC at 42 yr, 2 were asymptomatic at 41yr and 67yr (PMID 20013610).
276	43613847	Exon 13	c.2311G>A	p.D771N	Uncertain	Unknown		▶ First report, individual described as having FMTC diagnosis, but no patient/clinical information given (PMID 21542403). Variants were detected by scanning 21 RET exons by heteroduplex single-strand conformation polymorphism analysis. Second report, variant was found in two unrelated HSCR patients (PMID 11436122). Functional studies: lower p.D771N RET activity than WT (loss of function) and no transformation activity (PMID 22837065), so p.D771N is likely benign for MEN2.
278	43613866	Exon 13	c.2330A>G	p.N777S	Uncertain	Unknown	60	▶ Family had 4 with the variant: 1 had MTC (60 yr). Functional studies:RET activity (PMID 16384843).
280	43613868	Exon 13	c.2332G>A see comments	p.V778I	Uncertain	Unknown	42	▶ First report, Chinese family where p.V778I was an incidental finding in a large MEN2A pedigree: p.V778I was heterozygous in 7 family members and none had MTC (PMID 27798940,). Second report, Italian family had 2 with variant genotype: 1 had MTC at 42yr (PMID 30927507). Third report, Spanish family had p.V778I in cis with p.V804M in 5 family members, genotype c.[2332G>A;2410G>A]: 3 had MTC (PMID 11732489). Individuals may also have corneal nerve thickening. Fourth report, individual was homozygous for p.V778I, genotype c.2332[G>A];[G>A]: MTC at 72 yr (PMID 12016484).
286	43613878	Exon 13	c.2342A>G see comments	p.Q781R	Uncertain	Unknown	71	▶ First report, family had 2 with the variant: 2 had MTC (PMID 12072055). Second report, French individual with MTC at 73 yr (PMID 28946813). Third report, family had 2 with variant genotype: both asymptomatic at 64 and 31 yr (PMID 23468374). In this second family, p.Q781R was found in cis with a de novo p.V804M in one family member, genotype c.[2342A>G;2410G>A]: MTC, mucosal nodules, and diagnosed as MEN2B. Note, this is a more severe phenotype than either variant alone.
290	43613884	Exon 13	c.2348A>G	p.N783S	Uncertain	Unknown	57	▶ French individual with MTC at 57 yr; described as variant of uncertain significance (PMID 28946813).
292	43613900	Exon 13	c.2364C>T	p.I788=	likely benign	No MEN2 Disease		▶ Polish individual with MTC at 46 yr (PMID 28647780).
294	43613906	Exon 13	c.2370G>C	p.L790F	Pathogenic	Classical MEN2A; or Unclassified MEN2		▶ Report of three siblings with MTC only (PMID 9506724). Additional references: PMID 16314641, 18062802 and 12490841.
296	43613906	Exon 13	c.2370G>T	p.L790F	Pathogenic	Classical MEN2A; or Unclassified MEN2	14	▶ Youngest with MTC 14 and 16 yr (PMID 32411094 and 16865646). Reports of PHEOs; youngest at 28 yr (PMID 9506724, 22403753, 30877234, and 9167962). Functional studies PMID 30653460 and 21810974. Additional references: PMID 12409662, 12193298, 12490841, and 18062802. Has been found with another RET change, see p.K603Q entry.
298	43613907	Exon 13	c.2371T>A	p.Y791N	Uncertain	Unknown	25	▶ First report, family had least 4 with the variant: 1 had HSCR; otherwise no evidence of MEN2 disease in family (PMID 17108762). Second report, family had 2 with the variant: both asymptomatic at 46yr and 72yr (PMID 20013610). Third report, family had 1 with the variant genotype: MTC at 25 yr (MEN2008 meeting poster 52 http://www.hormones.gr/preview.php?c_id=654). Fourth report, French individual with MTC at 58 yr (PMID 28946813).
300	43613908	Exon 13	c.2372A>T	p.Y791F	Benign	No MEN2 Disease		▶ PMID 19906784, 30644554, and 25425582 indicate p.Y791F is a rare non-pathogenic polymorphism rather than a disease-causing mutation. GnomAD frequency 0.21% (1.6% Ashkenazi Jewish cohort) is very common for an uncommon disease. Functional studies: PMID 15753368, 27704398, 22837065, and 17102091. p.Y791F was also found in HSCR patients (PMID 9090527, 12566528 and 17021738). Additional references: PMID 12205548, 19826964, 16388093, 17483988, 18058472, 25950813, and 18062802.
302	43614996	Exon 14	c.2410G>A see comments	p.V804M	Pathogenic	Classical MEN2A; MEN2A with CLA; or FMTC	6	▶ 6 yr old had metastatic MTC (PMID 11114642). Youngest with PHEO: 28 yr (https://onlinelibrary.wiley.com/doi/pdf/10.1111/j.1365-2796.2004.01343.x). Youngest with HPT: 55 yr (PMID 15386323). p.V804M may have variable penetrance (PMID 10876191 and 11114642). Reports of homozygosity (PMID 12019403 and 15741265). Reports of cutaneous lichen amyloidosis and corneal nerve thickening (PMID 20497437 and 19445625). Functional studies: RET activation (PMID 30653460, 21810974, 10679286, 17047083, and 16469774). Additional references: PMID 17316110, 19958926, 17466010 and 9452077. Has been found with other RET changes, see p.E768D (c.2304G>T), p.V778I, p.Q781R, p.E805K, p.Y806C, p.Y826S, p.R844L, p.S904C, and p.I944M.
304	43614996	Exon 14	c.2410G>C	p.V804L	Pathogenic	Unclassified MEN2		▶ Family report, 2 with the variant: 2 had MTC (54 yr and age not given). References: PMID 9384613, 11114642, and https://onlinelibrary.wiley.com/doi/pdf/10.1111/j.1365-2796.2004.01343.x. Has been found with another RET change, see p.V648I.
306	43614996	Exon 14	c.2410G>T see comments	p.V804L	Pathogenic	Classical MEN2A; or FMTC	12	▶ The 12 yr old with metastatic MTC also had somatic p.M918T variant (PMID 11932300). Youngest with PHEO: 38 yr (PMID 33362715). Youngest with HPT: 9 yr (PMID 16813623). FMTC phenotype is more common, only three family reports of MEN2A (PMID 16813623, 10235148 and 16343097); and one report of homozygosity causing MEN2A (PMID 15741265). Functional studies: RET activation (PMID 9242375 and 10445857). Additional references: PMID 7784092, 20497437, 11114642 and 9384613.
310	43614997	Exon 14	c.2411T>C	p.V804A	Likely Pathogenic	Unknown		▶ Variant found in one Mexican-American individual in a cancer-free control cohort; clinical information was unavailable (PMID 25425582).
311	43614999	Exon 14	c.2413G>A see comments	p.E805K	Uncertain	Unknown	50	▶ No reports of p.E805K alone. MEN2B individual report, p.E805K was found in cis with p.V804M, genotype c.[2410G>A;2413G>A]; Metastatic MTC at 50 yr, PHEO, CNT, Marfanoid habitus, and prominent nodules on lips and tongue. Note, this is a more severe phenotype than the p.V804M variant alone. Functional studies: low RET oncogenic activation for E805K alone, while higher activation with p.V804M/E805K (PMID 17047083).
314	43615003	Exon 14	c.2417A>G see comments	p.Y806C	Uncertain	Unknown		▶ Japanese family report, 2 with variant genotype: both asymptomatic (27 and 51 yr). In this family, p.Y806C was also found in cis with de novo p.V804M in one family member with MEN2B, genotype c.[2410G>A;2417A>G]: MTC (23 yr), Marfanoid habitus, bumpy lips, mucosal neuroma, and thickening of corneal nerves. In another report on this same family (PMID 25759805), proband's daughter has both p.Y806C and p.V804M: MEN2B with MTC at 8 yrs. Note, this is a more severe phenotype than either variant alone. Functional studies: p.Y806C results in low RET activity, yet synergistic, high activation with p.V804M/Y806C (PMID 10679286).
318	43615038	Exon 14	c.2452G>A	p.E818K	Uncertain	Unknown		▶ First report, individual with MTC only; listed as a codon 819 variant in the reference (PMID 18058472). Described as a variant of unknown significance (PMID 25637381).
319	43615042	Exon 14	c.2456G>T see comments	p.S819I	Uncertain	Unknown		▶ No reports of p.S819I alone. Caucasian individual has three RET sequence changes: p.D631Y, p.S819I, and p.E843D (Genotype c.[1891G>T(;)2456G>T(;)2529G>T]); metastatic MTC at 40 yr. Unknown if sequence changes are in cis or trans (PMID 11149622).
322	43615063	Exon 14	c.2477A>C see comments	p.Y826S	Uncertain	Unknown		▶ Family had 4 with p.Y826S variant only: asymptomatic at 12, 15, 38 and 72 yr (PMID 27099842). In this family, p.Y826S was found in trans with p.V804M in two family members, genotype c.[2410G>A];[2477A>C]: 1 had MTC at 44 yr. One family member had p.V804M only: C-cell hyperplasia at 18 yr.
323	43615083	Exon 14	c.2497C>T	p.R833C	Uncertain	Unknown	59	▶ First report, individual with MTC only at 59 yr (PMID 16469774). Functional studies: RET activation (PMID 16469774). Second report, Italian family had 2 with variant: 1 had MTC (PMID 31510104). Third report, individual with HPT; described as variant of uncertain significance (PMID 32430905).
324	43615094	Exon 14	c.2508C>T	p.S836=	Benign	No MEN2 Disease		▶ Common polymorphism, not causative of MEN2 disease. Functional studies: PMID 10980580. Additional references: PMID 18976163, 16118333, 11589684 and 16091499.
326	43615108	Exon 14	c.2522C>T	p.P841L	Uncertain	Unknown		▶ First report, individual with unilateral MTC only and no family history of MEN2 (https://onlinelibrary.wiley.com/doi/pdf/10.1111/j.1365-2796.2004.01343.x). Second report, Korean individual with PHEO only at 42 yr (PMID 24134185). Third report, variant was also found in two HSCR patients (PMID 12566528 and 22648184).
328	43615109	Exon 14	c.2523G>A	p.P841=	Benign	No MEN2 Disease		▶ First report, Japanese individual with MTC only (PMID 9223675). Second report, p.P841= was found in the germline of a 65yr old gastric cancer patient: No mention of MEN2 screening (PMID 17344846). Third report, Chinese individual with HSCR (PMID 22174939). Fourth report, Chinese individual with MTC at 39 yr (PMID 33827484).
331	43615115	Exon 14	c.2529G>T see comments	p.E843D	Uncertain	Unknown		▶ No reports of p.E843D alone. Caucasian individual has three sequence changes: p.D631Y, p.S819I, and p.E843D (Genotype c.[1891G>T(;)2456G>T(;)2529G>T]): metastatic MTC at 40 yr (PMID 11149622). Unknown if sequence changes are in cis or trans.
332	43615116	Exon 14	c.2530C>T	p.R844W	Uncertain	Unknown		▶ Germline variant found in a Korean sporadic HSCR patient; not screened for MEN2 (PMID 16818057).
334	43615117	Exon 14	c.2531G>A	p.R844Q	Uncertain	Unknown	44	▶ First report, Polish individual with MTC only (PMID 18058472). Second report, Polish individual with MTC at 44yr (PMID 29386230). Third report, French individual with unilateral PHEO at 33 yr (PMID 30877234). Functional studies: PMID 29625052.
336	43615117	Exon 14	c.2531G>T see comments	p.R844L	Uncertain	unknown		▶ p.R844L was found in the germline of 57 yr old melanoma patient; no mention of MEN2 screening (PMID 17344846). In addition, p.R844L was found in cis with p.V804M, genotype c.[2410G>A;2531G>T] in two families. The first was a Prussian FMTC family that had 5 with both sequence changes: 4 had MTC (55 - 85 yr), 1 had C-cell hyperplasia (PMID 10826520). The second French family had 2 with both sequence changes: 2 had MTC both at 51 yr (PMID 28946813). Functional studies: PMID 29625052.
340	43615121	Exon 14	c.2535C>T	p.A845=	Likely Benign	No MEN2 Disease		▶ Individual with MTC only (PMID 11230481).
342	43615129	Exon 14	c.2543T>C	p.M848T	Uncertain	Unknown	67	▶ Italian individual with MTC at 67 yr (PMID 17895320). Functional studies: PMID 21810974. Addition reference: 31510104.
344	43615142	Exon 14	c.2556C>G see comments	p.I852M	Uncertain	Unknown	20	▶ First report, family had 2 with the variant: 1 had MTC at 20 yr (PMID 11295841). Second report, individual had MTC at 65 yr (database submission). Third report, family had 5 with the variant: 1 had MTC at 64 yr (PMID 21711375). Fourth report, p.I852M variant was found in cis with p.C634Y in three family members, genotype c.[1901G>A;2556C>G]: 1 had MTC, PHEO, and HPT (45 yr); 1 had MTC (7 yr); 1 had C-cell hyperplasia (10 yr) (PMID 26876062). Note that three recent reports indicate that p.I852M is likely benign (PMID 28578594, 31043326, and 29656518). For example, a Dutch family had 3 with the variant: 1 had MTC at 69 yr, 2 had C-cell hyperplasia at 39 and 42 yr. The MTC had a somatic RET variant [p.E632_V637delinsAA (c.1895_1910delinsCAGC)] that was likely responsible for the cancer development versus the germline p.I852M variant (PMID 28578594). Functional studies: PMID 21711375 and 29625052.
348	43615505	Intron 14	c.2608-24G>A		Benign	No MEN2 Disease		▶ Common polymorphism, not causative of MEN2 disease. Previously called IVS14-24G>A. Additional references: PMID 16118333, 18284634 and 12872262.
350	43615562	Exon 15	c.2641C>G	p.L881V	Uncertain	Unknown	46	▶ Family had 6 with the variant: 1 had metastatic MTC (46yr), 1 had unilateral/monofocal C-cell hyperplasia (20 yr), 1 had normal thyroid (17yr), 1 had elevated calcitonin (43yr), and 2 asymptomatic upon screening (>70 yr). Additional reference: PMID 20013610 and MEN2008 meeting poster 26 http://www.hormones.gr/preview.php?c_id=628.
352	43615568	Exon 15	c.2647G>A see comments	p.A883T	Uncertain	Unknown	68	▶ First report, French individual with MTC at 68 yr; and described as likely pathogenic (PMID 28946813). Second report, Italian family had 3 with variant: 1 had MTC; but also had heterozygous somatic deletion encompassing the 883 codon (PMID 31510104). Third report, family had 4 with variant: all asymptomatic at 82, 63, 58, and 15 yr (PMID 15531548). In this family, p.A883T was also found as homozygous in two family members, genotype c.2647[G>A];[G>A]: both had MTC (51 and 56 yr). Concluded that p.A883T has to be homozygous to cause MEN2. Functional studies: PMID 21810974 and 15531548.
356	43615568	Exon 15	c.2647_2648 delinsTT	p.A883F	Pathogenic	MEN2B	10	▶ p.A883F accounts for ~5% of known MEN2B causative variants. Youngest with MTC: 10 yr (PMID 15281979). Reports of five unrelated individuals with de novo p.A883F variant: 5 had MTC (10 yr-19yr), 3 had PHEO (11yr, 23yr and 34 yr), all had mucosal neuromas, and 4 had Marfanoid habitus (PMID 28323957, 9360560, 15281979, and 9294615). First family report, 2 had the p.A883F variant: 1 had MTC, 1 had C-cell hyperplasia (8 yr), and both had mucosal neuromas (PMID 28323957 and https://www.endocrine-abstracts.org/ea/0021/ea0021p219 [exact genotype not given]). Second family report, 2 had the p.A883F variant: 2 had MTC, 1 had PHEO (44 yr), and both had mucosal neuromas and Marfanoid habitus (PMID 28323957 and 24745698 [exact genotype not given]). Third family report, 4 had the p.A883F variant: 1 had MTC and PHEO (39 yr); 3 had C-cell hyperplasia or normal thyroid at surgery (7, 7 and 9 yr); 2 had mucosal neuromas (PMID 21186952 and 28323957). Functional studies for p.A883F: RET activation (PMID 10679286, 17047083, 21711375, and 10445857 [exact genotype not given in all references]).
358	43615577	Exon 15	c.2656C>T	p.R886W	Likely Pathogenic	Unknown	44	▶ Portuguese family had 2 with the variant: 1 had MTC at 44 yr (PMID 16712668). Functional studies: RET activation, PMID 21551259.
360	43615592	Exon 15	c.2671T>G	p.S891A	Pathogenic	Classical MEN2A; or FMTC	13	▶ Youngest MTC at 13 yr (PMID 14561794). Reports of PHEO (youngest 41 yr), parathyroid hyperplasia (youngest 17 yr), and corneal nerve thickening (PMID 30927507, 20554711, 15292360, 17178962, and 12686527). Functional studies: RET activation (PMID 10445857, 16469774, and 15753368). Additional references: PMID 18062802, 9398735, and 17895320. Has been found with another RET change, see p.R525W.
362	43615594	Exon 15	c.2673G>A see comments	p.S891=	Benign	No MEN2 Disease		▶ First report, synonymous variant was found in a DNA sample from the general population; no patient/clinical information (personal communication). Second report, Polish individual with MTC at 58 yr (PMID 28647780). Third report, Polish individual had p.S891= and p.C618S, genotype c.[1853G>C(;)2673G>A] (Unknown if sequence changes are in cis or trans): MTC at 37 yr.
364	43615613	Exon 15	c.2692G>T	p.D898Y	Uncertain	Unknown		▶ Korean family had 4 with the variant: 1 had unilateral PHEO (49 yr), 1 had papillary thyroid cancer (PMID 29850289).
365	43615632	Exon 15	c.2711C>G see comments	p.S904C	Uncertain	Unknown		▶ No reports of p.S904C alone. Single family report, p.S904C was found in cis with p.V804M in 5 family members, genotype c.[2410G>A;2711C>G]: 2 had MTC, 1 had HPT (uncharacteristic for MEN2B), 2 with mucosal neurilemmomas (characteristic for MEN2B). Phenotype described as atypical MEN2B. Note, this is a more severe phenotype than the p.V804M variant alone (PMID 11788682).
368	43615632	Exon 15	c.2711C>T	p.S904F	Likely Pathogenic	FMTC; or Unclassified MEN2	28	▶ First report, Italian individual with MTC only at 40 yr (PMID 17895320). Second report, family had 2 with the variant: both MTC (PMID 21810974). Third report, Italian family had 2 with the variant: 1 had MTC only (50 yr), 1 had MTC (31 yr) and prolactin-secreting PA pituitary adenoma (49 yr) [www.yumpu.com/en/document/read/10650565]. Fourth report, family had 8 carriers and 2 obligate carriers with the variant: 7 had MTC (PMID 33167350). Functional studies: PMID 21810974.
370	43615633	Exon 15	c.2712C>G	p.S904=	Benign	No MEN2 Disease		▶ Common polymorphism, not causative of MEN2 disease. References: PMID 16118333, 16091499, 12702567, 18976163 and 15531548.
372	43615640	Exon 15	c.2719A>G	p.K907E	Uncertain	Unknown		▶ First report, individual with sporadic HSCR; not screened for MEN2 (PMID 7581377). Second report, individual with sporadic HSCR and p.K907E (exact genotype not given): no MEN2 association (PMID 10790203). Functional studies: abolish RET activity (PMID 9502784), so p.K907E is likely benign for MEN2.
374	43615641	Exon 15	c.2720A>T	p.K907M	Uncertain	Unknown		▶ Two reports with limited patient/clinical information: individual with MTC only (PMID 11688458); and family with no MTC (PMID 18976163).
376	43617398	Exon 16	c.2735G>A	p.R912Q	Uncertain	Unknown		▶ Germline variant found in a German sporadic HSCR patient; not screened for MEN2 (PMID 11955539). Functional studies: lower p.R912Q RET activity than WT (potential loss of function) and no transformation activity (PMID 22837065), so p.R912Q is likely benign for MEN2.
378	43617398	Exon 16	c.2735G>C	p.R912P	Uncertain	Unknown	14	▶ First report, family had 12 with the variant: 2 had MTC (45 yr and 14 yr). The 14 yr old had metastatic MTC and was the only family member with skeletal abnormalities (PMID 15240641). Second report, individual with MTC only (PMID 18058472). Functional studies: PMID 29625052.
380	43617415	Exon 16	c.2752A>G	p.M918V	Uncertain see comments	Unknown	24	▶ Although classified as Uncertain, the p.M918V variant is leaning towards Likely Pathogenic. There was enough pathogenic evidences for Likely Pathogenic classification, but the functional studies demonstrated conflicting findings (PMID 21810974, 30653460, and 9075701); resulting in the Uncertain variant classification. First report, individual with MTC (PMID 25440022). Second report, Italian individual with MTC at 30 yr (PMID 30927507). Third report, French individual with MTC at 56 yr; described as likely pathogenic and moderate risk (PMID 28946813). Fourth report, Chinese individual with MTC at 69 yr; described as pathogenic (PMID 33827484). Eight Brazilian family reports (with a Portuguese founder mutation) had 42 with the variant: 21 MTC (24 to 59 yr). No variant carrier had PHEO, HPT, HSCR, or the MEN2B non-endocrine features (PMID 27807060 and 30763276).
382	43617416	Exon 16	c.2753T>C	p.M918T	Pathogenic	MEN2B	0.17	▶ p.M918T accounts for ~94% of known MEN2B causative variants. Youngest age of onset for MTC is 9 weeks (PMID 17848262 and 22992277), and for PHEO is 10 yr (PMID 30113649). One or more characteristic MEN2B non-endocrine clinical features may also manifest: such as mucosal ganglioneuromas, GI ganglioneuromas, eye abnormalities including corneal nerve thickening, or skeletal abnormalities including Marfanoid habitus. Functional studies: high RET activation (PMID 7824936, 9242375, 10679286, 10445857). In the oldest reference, codon 918 was called codon 664. Additional references: PMID 19240193, 8880581, 15281979 and 7906417. Has been found with other RET changes; see p.S922Y.
386	43617428	Exon 16	c.2765C>A see comments	p.S922Y	Uncertain	Unknown		▶ First report, family had 3 with the variant: all asymptomatic (PMID 8595427). In this family, p.S922Y was also found in cis with p.M918T in one family member, genotype c.[2753T>C;2765C>A]: MEN2B. Second report, Japanese family had p.S922Y was in cis with rs2435357T (known enhancer mutation in RET intron 1) in 8 family members: 5 HSCR (PMID 28799054).
389	43619149	Exon 17	c.2832C>G see comments	p.I944M	Uncertain	Unknown		▶ No reports of p.I944M alone. Family report (PMID 30936199), p.I944M was found in cis with p.V804M in 5 family members, genotype c.[2410G>A;2832C>G]: 1 had MTC (43 yr), 1 had mildly elevated calcitonin (10yr), 3 were asymptomatic (3, 7, and 12 yr).
390	43620416	Exon 18	c.3025A>G	p.M1009V	Uncertain	Unknown		▶ South African individual described as having FTMC diagnosis, but no patient/clinical information given (PMID 21542403). Variants were detected by scanning 21 RET exons by heteroduplex single-strand conformation polymorphism analysis.
392	43622032	Exon 19	c.3049G>A	p.D1017N	Uncertain	Unknown		▶ South African individual described as having FTMC diagnosis, but no patient/clinical information given (PMID 21542403). Variants were detected by scanning 21 RET exons by heteroduplex single-strand conformation polymorphism analysis.
394	43622105	Exon 19	c.3122T>G	p.V1041G	Uncertain	Unknown		▶ South African individual described as having MEN2A diagnosis, but no patient/clinical information given (PMID 21542403). Variants were detected by scanning 21 RET exons by heteroduplex single-strand conformation polymorphism analysis.

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MEN2 Database

171 variants found