MEN2 Database

Family report, one has the mutation genotype: unilateral MTC and unilateral Pheo at 44 yr. Single individual report, p.V292M was found in the germline of a 45 yr old colorectal cancer patient: No mention of MEN2 screening (PMID 17344846). GnomAD frequency 0.06%, fairly common for uncommon disease (gnomad.broadinstitute.org/gene/ENSG00000165731). Has been found with other RET changes, see the other p.V292M entries.

p.V292M mutation was found in cis with two other RET changes (p.R67H and p.R982C) in a Chinese family, genotype c.[200G>A;874G>A;2944C>T]. Family members with only the p.V292M/R67H/R982C allele had MTC (70 yr) and C-cell hyperplasia (44 yr). Variants p.R67H and p.R982C are common and likely benign, GnomAD frequency 0.1% and 2%, respectively (gnomad.broadinstitute.org/gene/ENSG00000165731). In this family, the p.V292M/R67H/R982C allele was also found in trans with p.C634Y mutation, see next p.V292M entry. For reports of p.V292M alone, see first p.V292M entry.

The 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]. One family member had both variant RET alleles and MTC onset at 13 yrs. Family members with only the p.C634Y mutation had MEN2A. Family members with the p.V292M/R67H/R982C allele had MTC (70 yr) and C-cell hyperplasia (44 yr). Variants p.R67H and p.R982C are common and likely benign, GnomAD frequency 0.1% and 2%, respectively (gnomad.broadinstitute.org/gene/ENSG00000165731). For reports of p.V292M alone, see first p.V292M entry.

Single French individual report: MTC at 49 yr.

Single Czech family report, 4 have the variant genotype: 1 metastatic MTC (61 yr), 1 bi-lateral C-cell hyperplasia (42 yr).

First report, single individual: HSCR. Second report, single family, two with mutation genotype: 1 MTC only (PMID 21810974). Third report, single individual: MTC (PMID 21054478). Additional references: PMID 20516206 and 31510104. In vitro studies: PMID 21810974 and 25440022

Single family report of de novo mutation, one with mutation genotype: MTC (37 yr) and bilateral Pheo (31 yr). Mutation is an inframe deletion. Genotype was c.1512_1517delGGAGGG in the reference. In vitro studies indicated an activating mutation.

Single French individual report: MTC only (55 yr). Two unrelated French individual reports: 75 yr and 69 yr with MTC (PMID 28946813). GnomAD frequency 0.027%, fairly common for uncommon disease (gnomad.broadinstitute.org/gene/ENSG00000165731).

First report, single French individual: MTC only (66 yr). Second report, single Portuguese family, 4 have the variant genotype: 1 MTC (65 yr), 3 asymptomatic (49, 51, and 56 yr). Two unrelated French individual reports: 38 yr and 73 yr with MTC (PMID 28946813). In vitro studies: PMID 21551259. Present in GnomAD at 0.018%, fairly common for uncommon disease (gnomad.broadinstitute.org/gene/ENSG00000165731).

Single individual report: MTC (60 yr). Silent variant is described as likely benign.

Single Italian family report, 2 have the mutation genotype: 2 MTC (35 yr and 58 yr).

Single French individual report: MTC only (49 yr). Described as likely pathogenic.

Single family report, 9 have the mutation genotype (of which 1 was homozygous for the mutation). Homozygous individual had hemithyroidectomy at 27 yr, then complete thyroidectomy with identified MTC at 60 yr. Heterozygous individual had unilateral MTC at 63 yr. Other 7 heterozygous carriers no symptoms or surgery. In vitro studies indicated significant RET activation with mutation versus wild type.

p.R525W was found in one Brazilian individual in a cancer-free control cohort (0.08%). Individual/clinical information was unavailable. GnomAD frequency 0.001% (gnomad.broadinstitute.org/gene/ENSG00000165731). Variant is likely benign. Single family report, 2 have the variant genotype: both no surgery and no symptoms at 30 yr and 32 yr (PMID 26356818). In this family, p.R525W was found in trans with another RET change, see other p.R525W entry.

p.R525W was found in trans with p.S891A in two family members, genotype c.[1573C>T ];[ 2671T>G]: both had MTC (58 yr and 65 yr). Two other family members had p.R525W only: both no surgery and no symptoms at 30 yr and 32 yr. For reports of p.R525W alone, see first p.R525W entry.

Single family report, 4 have the mutation genotype: 4 MTC. Patients may also have corneal nerve thickening.

Single French individual report: MTC only (53 yr). Two unrelated French individual reports: 58 yr and 59 yr with MTC (PMID 28946813). Single Portuguese family, two have the mutation genotype: 1 MTC (64 yr), 2 bi-lateral Pheos (44 and 53 yr, 50 and 64 yr) PMID 27838608.

Variant found in a Thai sporadic HSCR patient. Not screened for MEN2. Patient also had Down syndrome (2-10% have HSCR).

Youngest with MTC 21 yr (metastatic). Youngest with Pheo 29 yr. Greek and Spanish/Brazil family reports. One patient was homozygous for mutation and had metastatic MTC at 26 yr. p.G533C may have variable penetrance. Specific RET polymorphisms may modify phenotype (PMID 19138318). Additional references: PMID 16649977, 23461807, 23745650, 18805915, and 17704047.

Single Macedonian individual report: MTC only (39 yr). This patient had the p.L534= germline and the additional p.A680T (c.2038G>A) somatic change in the MTC tissue.

Suspicion of MEN2B and HSCR before 1 year age, but further clinical information was unavailable. Asymptomatic parents were not tested for mutation. Described as likely pathogenic.

Two unrelated French individual reports: 1 MTC only (53 yr), and 1 with MTC and Pheo (53 yr). Described as VUS.

Single family report, 3 have the variant genotype: 1 MTC (32 yr), 2 asymptomatic (mother and sister).

Single individual report: metastatic MTC (68 yr). Reference called sequence change, IVS9-11G>A, using RET GenBank sequence AJ243297.

Single Spanish family report, 6 have the variant genotype: 1 MTC (46 yr), 4 asymptomatic (52, 50, 45, 19 yr), and 73 yr old not screened. Position not conserved or close to functional domains. p.R600Q is likely a rare polymorphism. Genotype is listed as c.1730G>A in reference.

Single Caucasian family report, 3 have the variant genotype: 1 metastatic MTC (35 yr), 2 micropapillary carcinoma. In vitro studies: PMID 15277225. Has been found with another RET change, see other p.K603Q entry.

p.K603Q was found with p.L790F in one French individual, genotype c.[1807A>C(;)2370G>T]: MTC (60 yr). Unknown if sequence changes are in cis or trans. For reports of p.K603Q alone, see first p.K603Q entry.

First single family report, 2 have the variant genotype: 1 MTC. Second report, single individual: bilateral/multifocal MTC (58 yr). In vitro studies: RET activation (PMID 18248647).

Single German individual report: HSCR only, thyroid was normal at 30 yr. No MEN2 symptoms reported. Additional reference: PMID 15326638. Although this patient appeared unaffected by MEN2, p.C609S is likely an MEN2 causative mutation, since the other genotype for p.C609S (c.1826G>C) is an MEN2 causative mutation.

MEN2A or FMTC families. Youngest with MTC: 27 yr. Youngest with Pheo: 22 yr (PMID 15771139). Patients may also have HSCR (PMID 10982477, 17895320 and 17188172). In vitro studies: RET activation (PMID 9879991). Additional references: PMID 20979234, 14561794 and 16707008.

Three family reports, 6 have the mutation genotype: 5 MTC and 4 Pheo (PMID 20979234). Additional references: PMID 12037758, 18063059 and 15326638.

MEN2A or FMTC families. Youngest with MTC: 14 yr. Youngest with Pheo: 27 yr. Youngest with HPT: 38 yr. Patients may also have HSCR or corneal nerve thickening (PMID 9498388, 8855832, 7633441, 12686527, 17021738 and 15531714). In vitro studies: RET activation (PMID 9230192). Additional references: PMID 20979234, 19472011, 10462620, 18063059 and 9384613. Has been found with another RET change, see c.1846_1848delGAG.

Youngest with Pheo 19 yr. Two family reports, 18 have the mutation genotype: 14 MTC, 4 Pheo, and 2 HPT (PMID 20979234). In vitro studies: RET activation (PMID 16343103). Additional references: PMID 19475497, 12050290, 18976013 and 15452453.

Family reports with MTC and Pheo (PMID 22734615 and 20979234). Youngest with Pheo 33yr. Additional references: PMID 18058472 and 14718397.

This variant has been reported to cause HSCR, not MEN2. In vitro studies: PMID 9502784 and 9230192. Additional references: PMID 7581377 and 11694544.

Single Polish family report, three have the variant phenotype: one had monofocal MTC (10 yr), 2 were asymptomatic (34 yr and 7 yr). Likely benign for MEN2 due to silent change.

Reported as causative of MEN2, no patient/clinical information (PMID 14718397).

Reported as causative of MEN2, limited patient/clinical information. Patients may also have HSCR (PMID 11694544). Single individual report: bilateral Pheo at 57 yr (PMID 19029228). Second individual with MTC at 30 yr and p.C611R (exact genotype not given, PMID 30624503). Additional references: PMID 12686527 and 9068588.

Single Spanish family report, 4 have the mutation genotype: 3 MTC (28 yr old had metastatic MTC), 1 C-cell hyperplasia. Has also been described as FMTC mutation, PMID 11073534.

Youngest with Pheo 26 yr (PMID 25379023). Patients may also have CLA (PMID 30300539). In vitro studies: PMID 9230192. Additional references: PMID 20979234, 20063095, 10951350, 8855832, and 18062802.

Single family report: 5 have the mutation genotype: 4 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.

No known families with this sequence change. Likely pathogenic due to the other p.C611S associated genotypes being pathogenic.

Single Japanese family report, 3 have the mutation genotype: 2 MTC, 1 suspected Pheo, 1 HSCR. Additional reference: PMID 19318731.

MTC common, one case of Pheo (PMID 19258401). Additional references: PMID 20979234, 11230481, 19258401 and 11331212.

One Spanish family report, 4 have the mutation genotype: 3 MTC (PMID 20979234).

In vitro studies: PMID 9230192. In the oldest reference, exon 10 was called exon 7. Additional references: PMID 20979234, 14739494, 11502806, and 7916559.

Single family report, 3 have the variant genotype: 1 unilateral Pheo (42 yr) with bilateral CCH (43yr), 1 neonatal HSCR, and 1 unaffected.

Single family report, 3 have the variant genotype: all asymptomatic. In this family, deletion was also found in trans with another RET change, see other c.1846_1848delGAG entry.

Codon 616 deletion was found in trans with p.C609Y mutation, genotype c.[1826G>A];[1846_1848delGAG]. Single family report, 2 have both sequence changes: 2 MTC. Three other family members with the codon 616 deletion only were asymptomatic.

MEN2A or FMTC families. Youngest with MTC: 9 yr. Youngest with Pheo: 29 yr. Patients may also have HSCR (PMID 9384613, 9498388 and 7716719). In the oldest reference, exon 10 was called exon 7. Additional references: PMID 7874109, 20979234, 20119574, 18062802 and 8849576. Has been found with another RET change, see p.E623K.

Youngest with Pheo 19 yr. Patients may also have HSCR, which occurs in ~33% of p.C618R families (PMID 7881414, 8675603 and 9259198). In vitro studies: RET activation (PMID 9879991 and 9230192). In the oldest reference, exon 10 was called exon 7. Additional references: PMID 17895320, 18063059 and 11935126.

Youngest with Pheo 22 yr. In vitro studies: PMID 9230192. In the oldest reference, codon 618 was called codon 364. Additional references: PMID 8640806, 16325365, 18063059 and 18062802.

Report of Pheo (PMID 7608256). Three family reports, 6 have the mutation genotype: 6 MTC and 1 Pheo (PMID 20979234). In vitro studies: PMID 9230192. In the oldest reference, exon 10 was called exon 7. Additional references: PMID 9699127 and 11230481. Has been found with another RET change, see p.D631D.

Average age for youngest MTC, 8 yrs (PMID 29656518). Seven family reports, 14 have the mutation genotype: 12 MTC and 2 Pheo (PMID 20979234). Patients may also have HSCR (PMID 9498388 and 9384613). In the oldest reference, codon 618 was called codon 364. Additional references: PMID 8625130, 9003111 and 15164440. Has been found with another RET change, see p.S891S.

Four family reports, 27 have the mutation genotype: 21 MTC, 2 Pheo, and 2 HPT (PMID 20979234). Additional references: PMID 9839497, 18063059, 7670926 and 19258401.

Two individual reports, no patient/clinical information. Reported as novel MEN2 mutation (PMID 14718397).

Single Dutch family, 3 have indel mutation: 1 MTC and Pheo, 1 HSCR. Genotype c.1857_1858delinsTC results in a silent change at codon 619 and a missense change at 620 (p.C620R). In the oldest reference, c.1858 was called 2052. Additional reference: PMID 9824583.

Few reports: limited patient/clinical information. Youngest with MTC: 38 yr. One patient had a family history of MEN2A. Additional references: PMID 11238493, 18062802 and 14718397.

Youngest with Pheo 19 yr (PMID 18063059). Patients may also have HSCR (PMID 17021738, 7881414 and 8909322). In vitro studies: PMID 14715928, 9879991 and 9230192. In the oldest reference, exon 10 was called exon 7. Additional references: PMID 20979234, 20152359, 12711285 and 17316110. Has been found with another RET change, see c.1857_1858delinsTC.

Three family reports, 13 have the mutation genotype: 7 MTC, 1 Pheo, and 4 HSCR (PMID 20979234). Additional references: PMID 11073534, 11502806 and 14718397.

In vitro studies: PMID 9230192. In the oldest reference, exon 10 was called exon 7. Additional references: PMID 9820617, 20979234, 18063059, 16868135 and 8797874.

Four family reports, 8 have the mutation genotype: 14 MTC and 3 Pheo (PMID 20979234). Patients may also have HSCR (PMID 9681852, 9745455 and 10549772). Additional references: PMID 18062802 and 14517954.

Three family reports, 8 have the mutation genotype: 3 MTC and 2 Pheo (PMID 20979234). Additional references: PMID 8909322, 18976013, 19443294, 18063059 and 7874109. Has been found with another RET change, see other p.C620F entry.

p.C620F mutation was found in cis with p.Y791F variant in a Czech MEN2A family, genotype c.[1859G>T;2372A>T]. 58 yr old had metastatic MTC. Additional reference: PMID 19826964. For reports of p.C620F alone, see first p.C620F entry.

Single individual report of de novo indel mutation p.C620L: MTC at 19 yr. p.C620L is likely an MEN2 causative mutation due to loss of cysteine at codon 620.

Patients may also have HSCR (PMID 9384613). Additional references: PMID 20979234, 20152359, 17270543 and 14718397.

Single French individual report: MTC and Pheo at 70 yr. This silent variant is described as likely benign.

Single individual report: described as having inherited MTC (no patient/clinical information). p.E623K was called a rare silent polymorphism. Single family report, 3 have the variant genotype: all asymptomatic (PMID 15858153). In this family, p.E623K was also found in trans with the p.C618S mutation, see other p.E623K entry.

p.E623K was found in trans with p.C618S mutation, genotype c.[1852T>A];[1867G>A]. Single family report, 2 have both sequence changes: 2 MTC. Four other family members with p.E623K only were asymptomatic. For more reports of p.E623K alone, see first p.E623K entry.

Single individual report of thyroid cancer: potential MTC (see reference). Previously called IVS10+4G.

Youngest with MTC: 10 yr. One case of HPT (PMID 15523405). In vitro studies: RET activation (PMID 9879991). Additional references: PMID 16053382 and 30763276.

Few reports: MTC only and one case of HPT. Additional references: PMID 17527003 and 17895320.

Single Japanese individual report: MTC only (39 yr). p.C630S is likely an MEN2 causative mutation, due to the codon 630 location and patient had multifocal, bi-lateral MTC.

Single individual report: MTC only. Has also been described as FMTC mutation, PMID 11073534. In vitro studies: PMID 9230192.

Family report, 3 with variant genotype: 1 MTC (59 yr). In vitro studies: low to no RET activity (PMID 10049754).

Youngest with Pheo 22 yr. First report on two Korean families, 10 have the mutation genotype: 2 MTC, 4 Pheos (PMID 16839264). Only exons 10 - 11 were sequenced. Another family report, 7 with mutation genotype: 1 C-cell hyperplasia, 1 MTC, 3 Pheo, 1 HPT (PMID 22274720). Single Korean individual report: Pheo only at 71 yr (PMID 24134185). In vitro studies: RET activation (PMID 10049754). Additional references: PMID 14718397 and 18062802. Has been found with other RET changes, see other D631Y entries.

p.D631Y was found with p.Y791F sequence change, genotype c.[1891G>T(;)2372A>T]. Single French individual report: MTC and Pheo at 31 yr. Unknown if sequence changes are in cis or trans. p.Y791F is likely a benign polymorphism rather than a disease-causing mutation (PMID 19906784 and 25425582), see p.Y791F entries for more information. For reports of p.D631Y alone, see first p.D631Y entry.

Single Caucasian MEN2A patient has three sequence changes: p.D631Y, p.S819I, and p.E843D. Genotype c.[1891G>T(;)2456G>T(;)2529G>T]. Unknown if sequence changes are in cis or trans. Metastatic MTC at 40 yr. For reports of p.D631Y alone, see first p.D631Y entry.

In vitro studies only: low to no RET activity. No known families with this sequence change.

In vitro studies only: low to no RET activity (PMID 10049754). No known families with this sequence change. p.D631G was found as a somatic sequence change in a Japanese MTC patient.

Two individuals, no patient/clinical information. p.D631V has been found with another RET change, see p.H665Q entry.

Single family report, 14 have the mutation genotype: 12 MTC, 10 HPT, no Pheos. 12 bp duplication of codons 631-634. In vitro studies: RET activation (PMID 10918602).

Two reports: p.D631E was found with p.C634Y mutation, genotype c.[1893C>A(;)1901G>A]. Unknown if in cis or trans. Additional reference: PMID 15858153. No reports of p.D631E alone.

First individual report: lung cancer patient at 53 yr, no mention of MEN2 screening. Second individual report: clinically sporadic MTC (PMID 31510104). Likely benign for MEN2 due to silent change. GnomAD frequency 0.013%, fairly common for uncommon disease (gnomad.broadinstitute.org/gene/ENSG00000165731). Has been found with another RET change, see other p.D631= entry.

p.D631= was found with p.C618Y mutation, genotype c.[1853G>A(;)1893C>T]. Unknown if in cis or trans. No patient/clinical information. p.D631= is likely benign for MEN2 due to silent change. For report of p.D631= alone, see first p.D631= entry.

Single Chinese family report, 5 have the mutation genotype: 4 Pheo, 3 MTC, 1 asymptomatic (10yr). Youngest with MTC or Pheo: 31 yr. Deletion of 3 bp essentially causes loss of codon 631. Reference article is in Chinese. Reference in English: PMID 18845906.

Single German individual report: multifocal MTC at 53 yr. Single Italian individual with MTC (PMID 31510104 and 25440022).

Single Caucasian individual report: unilateral Pheo at 42 yr, no evidence of MTC

This indel changes three amino acids (ELC>DVR) which results in a p.C634R mutation. In vitro studies: RET activation (PMID 8612479). In the oldest reference, codon 634 was called codon 380. Additional reference: PMID 7595167.

Some families with Pheo or HPT (PMID 11524247). Additional references: PMID 11524247, 18058472, 15531714 and 7874109.

Youngest with MTC 17 months, Pheo 15 yr, and HPT 5 yr (PMID 11900218, 18063059, and 21449769). Only one family reported as FMTC (PMID 9950371). Patients may also have cutaneous lichen amyloidosis (PMID 12864791 and 7874109). In vitro studies: RET activation (PMID 9879991, 7824936, 9230192 and 9242375). In the oldest reference, exon 11 was called exon 8. Additional references: PMID 7595171, 7915822, 18063059, 18062802 and 18976013. Has been found with other RET changes, see p.A640G, p.V648I, p.M700L, p.S649L (c.1946C>T), and c.1896_1900delinsCGTGC.

Youngest with Pheo: 28 yr (PMID 19258401). Patients may also have cutaneous lichen amyloidosis (PMID 9111993). In the oldest reference, codon 634 was called codon 380. Additional references: PMID 12150334, 18062802, 19258401 and 18063059.

Single individual report: MTC, Pheo, and HPT at 56 yr. 9bp duplication of codons 634-636. In vitro studies: RET activation (PMID 10918602).

Youngest with MTC 10 months, Pheo 8 yr, and HPT 10 yr. Patients may also have cutaneous lichen amyloidosis (PMID 12864791, 7491519 and 7914213). In vitro studies: (PMID 9230192 and 7824936). In the oldest reference, codon 634 was called codon 380. Additional references: PMID 19240193, 11524247, 12711285, 18063059, 9820617 and 12604374. Has been found with other RET changes; see p.D631E, p.D707E, p.I852M, and the other p.C634Y entry.

p.C634Y mutation was found in cis with p.Y791F variant in four Brazilian MEN2A families, genotype c.[1901G>A;2372A>T]. The penetrance of MTC was 100% and Pheo was 84.6%, but only one case of HPT (50 yr). High prevalence of Pheo discussed by the authors as potentially caused by a modifying role of p.Y791F in patients with p.C634Y RET mutation. Another large Brazilian FMTC family that had the p.Y791F variant (PMID 17610518) was later discovered to also have the p.C634Y mutation in cis (PMID 23330657). Seventeen family members had genotype c.[1901G>A;c.2372A>T]: 10 had MTC (15 yr old had metastatic MTC), no Pheo or HPT upon screening. For reports of p.C634Y alone, see the first p.C634Y entry.

Youngest with MTC 4 yr (PMID 29656518). Youngest with Pheo 19 yr (PMID 28099363). In the oldest reference, codon 634 was called codon 380. Additional references: PMID 15277225, 8640806, 18062802 and 7874109. Has been found with another RET change, see p.A641S.

Youngest with MTC 3 yr (PMID 29656518). Youngest with Pheo 26 yr (PMID 25629635). Patients may also have cutaneous lichen amyloidosis (PMID 7874109). In the oldest reference, codon 634 was called codon 380. Additional references: PMID 16712668, 11900218, 15452453, 12604374 and 11524247.

Single French individual report: Pheo patient with personal/family history of MTC.

Youngest with Pheo: 18 yr (PMID 17898100, 23404858). Youngest with HPT: 5 yr (PMID 27406704). In vitro studies: PMID 8570194. Additional references: PMID 18794325, 11939755, 7915822, and 12788868. Has been found with another RET change, see p.R635G and p.S649L.

p.R635G was found with C634W mutation in two MEN2A families and two MTC patients, genotype c.[1902C>G(;)1903C>G]. Unknown if in cis or trans. Patients may also have CLA. In the oldest reference, c.1902 was called 2097. Additional references: PMID 12711285 and 8557249. No reports of p.R635G alone.

Single family report, 2 have the variant genotype: 1 unilateral Pheo only (41 yr), 1 asymptomatic (22 yr).

Single family report, 3 have the mutation genotype: 3 MTC. 1 bp deletion, 13 bp insertion mutation. Inserts ELCR after codon 635 with T636P change. In the reference, c.1906 was called 2101.

Single individual report: MTC only (78 yr)

p.A640G was found with p.M700L and also with known mutation p.C634R in an MEN2A patient, genotype c.[1900T>C;1919C>G;2098A>T]: MTC (26 yr) and Pheo. Daughter inherited no RET changes, so these three variants are likely in cis. Original report on patient where initially only p.C634R and p.A640G were found: PMID 10522989. No reports of p.A640G or p.M700L found alone.

p.A641S was found in cis with p.C634S mutation in an large MEN2A family, genotype c.[1901G>C;1921G>T]. No reports of p.A641S found alone.

Single French individual report: MTC (35 yr).

First family report, two with variant genotype: one C-cell hyperplasia, other no disease (PMID 21810974). In vitro studies: PMID 21810974. Three unrelated French individual reports: MTC at 21yr, 65 yr, and 68 yr (PMID 28946813). Described as likely benign. Two Italian individual reports: 1 had MTC and the other was unaffected (PMID 31510104). Second family report, 2 with the variant genotype: asymptomatic (22 and 37 yr, PMID 18209889). Third family report, 6 with the variant genotype: one had surgery at 52 yr, no MTC (PMID 26247112). In these last two families, p.V648I was also found in trans with other RET changes, see other p.V648I entries.

p.V648I was found in trans with p.C634R mutation in an MEN2A patient (MTC at 34 yr), genotype c.[1900T>C];[1942G>A]. Two other family members with p.V648I only were asymptomatic (22 and 37 yr, PMID 18209889). p.V648I is likely a rare polymorphism. For reports of p.V648I alone, see first p.V648I entry.

p.V648I was found in trans with p.V804L mutation in an MEN2A patient (MTC at 42 yr), genotype c.[1942G>A];[2410G>C]. Six other family members had p.V648I only: one had surgery at 52 yr, no MTC. One family member with p.V804L only, had surgery at <15 yr old, no MTC. p.V648I is likely a rare polymorphism. For reports of p.V648I alone, see first p.V648I entry.

PMID 19906784 and 29656518 indicates p.S649L is a rare non-pathogenic polymorphism rather than a disease-causing mutation. GnomAD frequency 0.033%, fairly common for uncommon disease (gnomad.broadinstitute.org/gene/ENSG00000165731). If mutation, p.S649L may have low or variable penetrance. Four individual reports: 2 MTC only, 1 HPT only (24 yr), 1 elevated calcitonin (47 yr). First family report, 5 have the variant genotype: 1 MTC only (69 yr). Second family report, 3 have the variant genotype: 2 asymptomatic (75, 41 yr), 1 elevated calcitonin (43 yr). In vitro studies (PMID 18322301). Additional references: PMID 15320968, 21551259, and MEN2 meeting poster P20 http://www.hormones.gr/preview.php?c_id=622. Has been found with other RET changes, see other p.S649L entries.

p.S649L was found in trans with p.C634R in a single Polish MEN2A patient, genotype c.[1900T>C];[1946C>T]. For reports of p.S649L alone, see first p.S649L entry.

p.S649L was found in trans with a de novo p.C634W in a single MEN2A patient, genotype c.[1902C>G];[1946C>T ]. Four family members had p.S649L only: 3 C-cell hyperplasia (64, 44, 20yr), 1 asymptomatic (60yr). For reports of p.S649L alone, see first p.S649L entry.

p.S649L was found with p.Y791F in a single HSCR patient, genotype c.[1946C>T(;)2372A>T]. Unknown if sequence changes are in cis or trans. For reports of p.S649L alone, see first p.S649L entry.

p.S649L was found in cis with p.V804L (genotype not published) in a individual with MTC. For reports of p.S649L alone, see first p.S649L entry.

Three reports of HSCR. Possible splicing variant, and may require another locus (PMID 10090908 and 10618407). One individual report of FMTC index patient with p.S649= (genotype not published, PMID 16118333). Likely benign for MEN2 due to silent change.

p.H665Q was found in cis with p.D631V sequence change, genotype c.[1892A>T;1995C>G]. Single family report, 4 have both sequence changes: 2 Pheo only, 2 asymptomatic. No reports of p.H665Q found alone. For reports of p.D631V alone, see p.D631V entry.

First family report, 8 with variant genotype: 3 MTC (57 yr, 49 yr, 35 yr), 2 C-cell hyperplasia (34 yr, 53 yr). Second family report, 2 with variant genotype: MTC (64 yr). Third family report, 5 with variant genotype: Pheo (35 yr). Single individual report: MTC at 64 yr (PMID 21690267). Additional reference: PMID 30927507.

Single French individual report: MTC and Pheo at 41 yr. Described as likely pathogenic.

Single individual report: MTC only (38 yr).

Single family report, 4 with the variant genotype: three had C-cell hyperplasia only (16, 41, 45yr), other no surgery (3 yr). Four additional family members have both an MEN1 (menin) mutation and the p.K666M RET change: 2 MTC (40 yr, 46 yr). Single Italian individual report: described as FMTC phenotype (PMID 20516206).

Single French individual report: MTC at 63 yr. Described as likely pathogenic.

Variant is likely pathogenic and associated with low disease penetrance. First report: French individual with MTC only at 65 yr. Second report: French individual with MTC only at 59 yr (PMID 28946813). Third report: single family, 6 with mutation: 2 MTC (55 yr, 70 yr). Seven unrelated individual cases with mutation 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). Fourth report: single individual with MTC and HPT at 54 yr (link.springer.com/journal/508/126/3/suppl/page/1 abstract P16). Fifth report: single family, 5 with heterozygous p.K666N mutation: 1 MTC (32 yr), 1 CCH (30 yr), and 3 are asymptomatic (25, 43, and 61yr), PMID 29408964. In this family, p.K666N was also found as homozygous in 1 family member, see the p.K666N c.1998G>T homozygous entry

Single family report: 1 with MTC and bi-lateral Pheo (58 yr) was homozygous for p.K666N, genotype c.1998[G>T];[G>T]. Five additional family members were only heterozygous for the mutation: 1 MTC (32 yr), 1 CCH (30 yr), and 3 are asymptomatic (25, 43, and 61yr). For more reports of heterozygous p.K666N, see first p.K666N c.1998G>T entry.

Indel mutates codon 666 (p.K666N due to codon sequence change AAG-AAT), then inserts a Serine. 12 yr old had metastatic MTC. Five Belgium family reports. Mutation may have variable penetrance. Single French individual report: MTC at 58 yr (PMID 28946813). Report of Pheo (www.endocrine-abstracts.org/ea/0011/ea0011p501.htm). In vitro studies: RET activation. Additional references: PMID 16954442 and www.endocrine-abstracts.org/ea/0011/ea0011p501.htm.

Single French individual report: MTC at 45 yr. This silent variant is described as likely benign. GnomAD frequency 0.11%, too common for uncommon disease, likely benign (gnomad.broadinstitute.org/gene/ENSG00000165731).

Single French individual report: MTC at 75 yr. This silent variant is described as likely benign. GnomAD frequency 0.026%, fairly common for uncommon disease, likely benign. (gnomad.broadinstitute.org/gene/ENSG00000165731). (Listed as c.2052G>A, p.P648P in reference).

Single Iranian family report, 2 have the variant genotype: 1 MTC and the other had a thyroidectomy due to thyroid nodules (18yr). Only RET exons 10, 11, and 16 were investigated.

Common polymorphism (11-33% allele frequency), not causative of MEN2 disease. Present in GnomAD at 21% (gnomad.broadinstitute.org/gene/ENSG00000165731). In vitro studies (PMID 18284634). Additional references: PMID 16118333, 16091499, 18976163, 19269918, 12702567 and 10022819.

Single French individual report: MTC at 62 yr. This silent variant is described as likely benign.

p.A640G was found with p.M700L and also with known mutation p.C634R in an MEN2A patient, genotype c.[1900T>C;1919C>G;2098A>T]: MTC (26 yr) and Pheo. Daughter inherited no RET changes, so these three variants are likely in cis. Original report on patient where initially only p.C634R and p.A640G were found: PMID 10522989. No reports of p.A640G or p.M700L found alone.

Single large Chinese family report, 15 with mutation: 8 MTC only (18-50 yr), 5 MTC and Pheo (26-50yr). Has has been found in cis with another RET change, see other p.D707E entry.

p.D707E mutation was found in cis with p.C634Y variant, genotype c.[1901G>A;2121T>A]. Single large Chinese family report, 33 have both sequence changes: 11 had MTC (range 14-65 yr), 4 had Pheo (median age 37 yr). For reports of p.D707E alone, see first p.D707E entry.

Two South African individuals in report: described as MEN2A diagnosis, but no patient/clinical information given. Variants were detected by scanning 21 RET exons by heteroduplex single-strand conformation polymorphism analysis.

FMTC phenotype is more common, only one report of Pheo (PMID 15855933). In vitro studies: RET activation (PMID 9242375). Additional references: PMID 7784092, 18062802, 9111992 and 15531714.

Three individual reports: MTC only. One patient had bilateral MTC. Additional references: PMID 12016484 and 12116277. Has been found with another RET change, see other p.E768D (c.2304G>T) entry.

p.E768D was found with p.V804M mutation, genotype c.[2304G>T(;)2410G>A]. Unknown if in cis or trans. Single individual report: MTC at 25 yr. For reports of p.E768D alone, see first p.E768D (c.2304G>T) entry.

Common polymorphism, not causative of MEN2 disease. Present in GnomAD at 74% (gnomad.broadinstitute.org/gene/ENSG00000165731). Additional references: PMID 16118333, 15531548, 18976163 and 16091499.

Single family report, 3 have the variant genotype: 1 MTC only (metastatic), 2 asymptomatic (41yr and 67yr).

Single individual report: described as FTMC diagnosis, but no patient/clinical information given. Variants were detected by scanning 21 RET exons by heteroduplex single-strand conformation polymorphism analysis. Variant was also found in two unrelated HSCR patients (PMID 11436122).

Single family report, 4 have the variant genotype: 1 MTC (60 yr). In vitro studies: low RET activity.

p.V778I was an incidental finding in a large Chinese pedigree with the p.D707E MEN2A mutation. p.V778I was not linked to p.D707E. p.V778I was heterozygous in 7 family members and none had MTC. Second Italian family report, 2 with variant genotype: 1 MTC at 42yr (PMID 30927507). Has been found with another RET change or homozygous, see other p.V778I entries.

Single individual report: MTC patient (72 yr) was homozygous for the p.V778I mutation, genotype c.2332[G>A];[G>A]. Limited patient/clinical information. For reports of heterozygous p.V778I only, see first p.V778I entry.

p.V778I was found in cis with p.V804M mutation, genotype c.[2332G>A;2410G>A]. Single Spanish family report, 5 have both sequence changes: 3 MTC. Patients may also have corneal nerve thickening. For reports of heterozygous p.V778I only, see first p.V778I entry.

First family report, 2 have the mutation genotype: 2 MTC. Single French Individual report: MTC at 73 yr (PMID 28946813). Second family report, 2 with variant genotype: asymptomatic at 64 and 31 yr (PMID 23468374). In this second family, p.Q781R was also found in cis with another RET change, see other p.Q781R entry.

p.Q781R was found in cis with p.V804M mutation, genotype c.[2342A>G;2410G>A]. Single family report, 1 has both sequence changes (p.V804M was de novo): MTC, mucosal nodules, and diagnosed as MEN2B. Two others have only the p.Q781R change only: asymptomatic (64 and 31 yr). For more reports of p.Q781R alone, see first p.Q781R entry.

Single French individual report: MTC at 57 yr. Described as variant of uncertain significance.

Single Polish individual report: MTC at 46 yr. Likely benign for MEN2 due to silent change.

Median age of MTC onset, 57 yr. Additional references: PMID 16314641, 18062802 and 12490841.

Youngest with MTC 16 yr (PMID 16865646). Youngest with Pheo: 28yr. Additional references: PMID 12409662, 12193298, 12490841 and 18062802. Has been found with another RET change, see p.K603Q entry.

First family report, at least 4 have the variant genotype: 1 HSCR. No evidence of MEN2 disease in family. Second family report, 2 have the variant genotype and were asymptomatic at 46yr and 72yr (PMID 20013610). Third family report, 1 has the variant genotype: MTC at 25 yr (MEN2008 meeting poster 52 http://www.hormones.gr/preview.php?c_id=654). Single French individual report: MTC at 58 yr (PMID 28946813).

PMID 19906784, 30644554, and 25425582 indicates p.Y791F is a rare non-pathogenic polymorphism rather than a disease-causing mutation. Present in GnomAD at 0.22%, too common for uncommon disease, likely benign (gnomad.broadinstitute.org/gene/ENSG00000165731). In vitro studies: PMID 15753368 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. Has been found with other RET changes, see p.C620F, p.C634Y, p.S649L, p.V804L (c.2410G>T), and p.M918T entries.

6 yr old had metastatic MTC. p.V804M may have variable penetrance (PMID 10876191 and 11114642). Reports of homozygous mutation (PMID 12019403 and 15741265). Reports of cutaneous lichen amyloidosis and corneal nerve thickening (PMID 20497437 and 19445625). 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.R844L (c.2531G>T), p.S904C (c.2711C>G), and p.I944M (c.2832C>G).

Single family report, two have the mutation genotype: 2 MTC (54 yr and not given). Additional references: PMID 9384613 and 11114642. Has been found with another RET change, see p.V648I.

The 12 yr old with metastatic MTC also had somatic p.M918T mutation (PMID 11932300). 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 homozygous mutation causing MEN2A (PMID 15741265). In vitro studies: RET activation (PMID 9242375 and 10445857). Additional references: PMID 20497437, 11114642 and 9384613. Has been found with another RET change, see other p.V804L (c.2410G>T) entry.

p.V804L mutation has been found in trans with p.Y791F in a single individual, genotype c.[2372A>T];[2410G>T]. Unknown phenotype for these mutations in trans (patient/clinical information was unavailable). For reports of p.V804L alone, see first p.V804L (c.2410G>T) entry.

Variant found in one Mexican-American individual in a cancer-free control cohort. Individual/clinical information was unavailable. Rare variant, not present in GnomAD (gnomad.broadinstitute.org/gene/ENSG00000165731).

p.E805K was found in cis with p.V804M mutation in an MEN2B patient, genotype c.[2410G>A;2413G>A]. Metastatic MTC at 50 yr. No reports of p.E805K alone.

Single Japanese family report, 2 with variant genotype: both asymptomatic (27 and 51 yr). Y806C results in low RET activity (PMID 10679286). In this family, p.Y806C was also found in cis with another RET change, see other p.Y806C entry.

p.Y806C was found in cis with p.V804M mutation in an Japanese MEN2B patient, genotype c.[2410G>A;2417A>G]. Patient had MTC at 23 yr. Two other family members with p.Y806C only were asymptomatic (27 and 51 yr). In another report on this family (PMID 25759805), proband's daughter has both mutations and MEN2B symptoms: MTC at 8 yrs. In vitro studies: p.Y806C results in low RET activity, yet synergistic with V804M (PMID 10679286).

Single individual report: MTC only. Listed as a codon 819 mutation in the reference.

Single Caucasian MEN2A patient has three sequence changes: p.D631Y, p.S819I, and p.E843D. Genotype c.1891G>T(;)2456G>T(;)2529G>T. Unknown if sequence changes are in cis or trans. Metastatic MTC at 40 yr. No reports of p.S819I alone.

Single individual report: MTC only at 59 yr. In vitro studies: low RET activation.

Common polymorphism (1-12% allele frequency), not causative of MEN2 disease. Present in GnomAD at 4.4% (gnomad.broadinstitute.org/gene/ENSG00000165731). In vitro studies: PMID 10980580. Additional references: PMID 18976163, 16118333, 11589684 and 16091499.

First report, single individual: MTC only. Patient had unilateral MTC and no family history of MEN2. Second report, single Korean individual: Pheo only at 42 yr (PMID 24134185). Variant was also found in a HSCR patient (PMID 12566528).

First report, single Japanese individual: MTC only. Second report, p.P841= was found in the germline of a 65yr old gastric cancer patient: No mention of MEN2 screening (PMID 17344846). Likely benign for MEN2 due to silent change. GnomAD frequency 0.011%, fairly common for uncommon disease (gnomad.broadinstitute.org/gene/ENSG00000165731).

Single Caucasian MEN2A patient has three sequence changes: p.D631Y, p.S819I, and p.E843D. Genotype c.[1891G>T(;)2456G>T(;)2529G>T]. Unknown if sequence changes are in cis or trans. Metastatic MTC at 40 yr. No reports of p.E843D alone.

Germline variant found in a Korean sporadic HSCR patient. Not screened for MEN2.

Single Polish individual report: MTC only. Another Polish individual: MTC only at 44yr, no other MEN2 symptoms (PMID 29386230).

R844L was found in the germline of 57yr old melanoma patient: No mention of MEN2 screening. Has been found with another RET change, see other p.R844L entry.

p.R844L was found in cis with p.V804M mutation, genotype c.[2410G>A;2531G>T] in two families. Single Prussian FMTC family report, 5 have both sequence changes: 4 MTC (55 - 85 yr), 1 C-cell hyperplasia. Single French family report, 2 have both sequence changes: 2 MTC both at 51 yr (PMID 28946813). For report of p.R844L alone, see first p.R844L entry.

Single individual report: MTC only. Likely benign for MEN2 due to silent change.

Single Italian individual report: MTC only (67 yr). In vitro studies: PMID 21810974.

First report: single family, 2 have the mutation: 1 MTC at 20 yr. Second report (database submission): single individual with MTC at 65 yr. Third report: single family, five have the mutation: 1 MTC at 64 yr. Three recent reports indicate that p.I852M is likely benign (PMID 28578594, 31043326, and 29656518). For example, in a single Dutch family, three have the mutation: 1 MTC at 69 yr, 2 with C-cell hyperplasia at 39 and 42 yr. The MTC had a somatic RET mutation that was likely responsible for the cancer development versus the germline p.I852M mutation (PMID 28578594). Present in GnomAD at 0.018%, fairly common for uncommon disease (gnomad.broadinstitute.org/gene/ENSG00000165731). In vitro studies indicate weakly activing mutation: PMID 21711375. Has been found with another RET change, see other p.I852M entry.

p.I852M variant was found in cis with p.C634Y mutation, genotype c.[1901G>A;2556C>G]. Single family report, three have both sequence changes: MTC, Pheo, HPT (45 yr), MTC (7 yr), and C-cell hyperplasia (10 yr). For reports of p.I852M alone, see first p.I852M entry.

Common polymorphism (6-28% allele frequency), not causative of MEN2 disease. Present in GnomAD at 20.4% (gnomad.broadinstitute.org/gene/ENSG00000165731). Previously called IVS14-24G>A. Additional references: PMID 16118333, 18284634 and 12872262.

Single family report, 6 have the variant genotype: 1 metastatic MTC (46yr), 1 uni-lateral/uni-focal C-cell hyperplasia (20 yr), 1 had normal thyroid (17yr), 1 elevated calcitonin (43yr), and 2 asymptomatic upon screening (>70 yr). Additional references: MEN2008 meeting poster 26 http://www.hormones.gr/preview.php?c_id=628.

Single French report: MTC at 68 yr. Described as likely pathogenic. Single family report, 4 with variant: all asymptomatic (82, 63, 58, 15 yr). In this family, A883T was also found as homozygous, see other p.A883T entry

Single family report: 2 with MTC (51 and 56 yr) were homozygous for p.A883T, genotype c.2647[G>A];[G>A]. 4 family members had only the heterozygous sequence variation and were asymptomatic (82, 63, 58, 15 yr). Concluded that p.A883T has to be homozygous to cause MEN2 disease. In vitro studies: PMID 21810974. For more reports of heterozygous p.A883T, see first p.A883T entry

p.A883F accounts for ~5% of known MEN2B mutations. Youngest with MTC: 10 yr. Youngest with Pheo: 11 yr. Five unrelated individual reports with de novo mutations: 5 MTC (10 yr-19yr), 3 Pheo (11yr, 23yr and 34 yr), all had mucusal neuromas, and 4 with marfaniod habitus (PMID 28323957). Family report, 2 with mutation genotype: 1 MTC (28 yr), 1 CCH (8 yr), both had mucosal neuromas. Family report, 2 with mutation genotype: 2 MTC, and 1 Pheo (44 yr), both had mucosal neuromas and marfanoid habitus. Family report, 4 with mutation genotype: 1 with MTC and Pheo (39 yr), 3 had CCH or normal thyroid at surgery (7, 7 and 9 yr), and 2 with mucosal neuromas (PMID 21186952 and 28323957). Additional references: PMID 9360560, 9294615, and 15281979.

Single Portuguese family report, 2 have the variant genotype: 1 MTC (44 yr). Additional reference and In vitro studies: PMID 21551259.

Reports of Pheo, parathyroid hyperplasia, and corneal nerve thickening (PMID 20554711, 15292360, 17178962, and 12686527). In vitro studies: RET activation (PMID 10445857 and 15753368). Additional references: PMID 18062802, 30927507, and 17895320. Has been found with another RET change, see p.R525W.

Silent sequence change was found in a DNA sample from the general population (personal communication). No patient/clinical information. Single Polish individual report: MTC at 58 yr (PMID 28647780). Likely benign for MEN2 due to silent change. GnomAD frequency 0.024%, fairly common for uncommon disease, likely benign (gnomad.broadinstitute.org/gene/ENSG00000165731). Has been found with another RET change, see other p.S891= entry.

p.S891= was found with p.C618S mutation, genotype c.[1853G>C(;)2673G>A]. Single Polish individual report, with both sequence changes: MTC at 37 yr. Unknown if sequence changes are in cis or trans. For reports of p.S891= alone, see first p.S891= entry.

p.S904C was found in cis with p.V804M mutation, genotype c.[2410G>A;2711C>G]. Phenotype described as atypical MEN2B. Single family report, 5 have both sequence changes: 2 MTC, 1 HPT (uncharacteristic for MEN2B), and mucosal neurilemmomas (characteristic for MEN2B). No reports of p.S904C alone.

First report, single Italian individual: MTC only (40 yr). Second report, single family, 2 with mutation: two MTC. Third report, single Italian family, 2 with mutation: 1 with MTC (50 yr), 1 with MTC (31 yr) and prolactin-secreting PA pituitary adenoma (49 yr) [www.yumpu.com/en/document/read/10650565]. In vitro studies: PMID 21810974.

Common polymorphism (11-27% allele frequency), not causative of MEN2 disease. Present in GnomAD at 21% (gnomad.broadinstitute.org/gene/ENSG00000165731). Additional references: PMID 16118333, 16091499, 12702567, 18976163 and 15531548.

First indivdual report: sporadic HSCR, not screened for MEN2. In vitro studies: abolish RET activity (PMID 9502784). Second individual report: sporadic HSCR and p.K907E (exact genotype not given), no MEN2 association (PMID 10790203). p.K907E is likely benign for MEN2.

Two reports with limited patient/clinical information. Single individual report: MTC only. Family report: no MTC (PMID 18976163).

Germline variant found in a German sporadic HSCR patient. Not screened for MEN2.

Single family report, 12 have the mutation genotype: 2 MTC. 14 yr old had metastatic MTC and was the only family member with skeletal abnormalities. Also a single individual report with MTC only (PMID 18058472).

Single family, 2 with mutation: one MTC. Single French individual with MTC at 56 yr. This mutation was described as likely pathogenic and moderate risk (PMID 28946813). Eight Brazilian family reports (Portuguese founder mutation), 42 with mutation: 21 MTC (24 - 59 yr). Two families had 2 members with MTC. One family has 9 members with MTC. No mutation carrier had Pheo, HPT, HSCR, or MEN2B features (PMID 27807060 and 30763276). In vitro studies: PMID 21810974 and 9075701.

p.M918T accounts for ~94% of known MEN2B mutations. Youngest age of onset for MTC is 9 weeks (PMID 17848262 and 22992277), Pheo 10 yr (PMID 30113649). In vitro 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 and other p.M918T entry.

p.M918T mutation was found in cis with p.Y791F variant in a Czech MEN2B family, genotype c.[2372A>T;2753T>C]. Additional reference: PMID 16705552. For reports of p.M918T alone, see first p.M918T entry.

Single family report, 3 with variant: all asymptomatic. In this family, p.S922Y was also found in cis with another RET change, see other p.S922Y entry.

p.S922Y was found in cis with p.M918T mutation in an MEN2B patient, genotype c.[2753T>C;2765C>A]. Three other family members with p.S922Y only were asymptomatic.

p.I944M was found in cis with p.V804M mutation in an MTC patient (43 yr), genotype c.[2410G>A;2832C>G]. Three other family members with both variants screened negative for symptoms at 7, 10 (mildly elevated calcitonin), and 12yr.

Single South African individual report: described as FTMC diagnosis, but no patient/clinical information given. Variants were detected by scanning 21 RET exons by heteroduplex single-strand conformation polymorphism analysis.

Single South African individual report: described as FTMC diagnosis, but no patient/clinical information given. Variants were detected by scanning 21 RET exons by heteroduplex single-strand conformation polymorphism analysis.

Single South African individual report: described as MEN2A diagnosis, but no patient/clinical information given. Variants were detected by scanning 21 RET exons by heteroduplex single-strand conformation polymorphism analysis.