ClinVar Miner

Submissions for variant NM_020975.6(RET):c.1900T>G (p.Cys634Gly) (rs75076352)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000182581 SCV000605032 pathogenic not provided 2018-01-03 criteria provided, single submitter clinical testing The RET c.1900T>G;p.Cys634Gly variant (rs75076352) has been published in multiple individuals and families with multiple endocrine neoplasia type 2 (MEN2) and familial medullary thyroid carcinoma (FMTC) and at least one individual with pheochromocytoma (American Thyroid Association Guidelines Task Force 2009, Hedayati 2011, Neumann 2002, Wells 2015). The variant is listed in the ClinVar database (Variation ID: 13908), but is not listed in the Genome Aggregation Database. The cysteine at codon 634 is conserved across a variety of species and computational programs (PolyPhen2, SIFT) predict this variant is deleterious to protein function. Considering available information, this variant is classified as pathogenic. References: American Thyroid Association Guidelines Task Force. Medullary thyroid cancer: management guidelines of the American Thyroid Association. Thyroid. 2009 19(6):565-612. Hedayati M et al. Predominant RET Germline Mutations in Exons 10, 11, and 16 in Iranian Patients with Hereditary Medullary Thyroid Carcinoma. J Thyroid Res. 2011:264248. Neumann HP et al. Germ-line mutations in nonsyndromic pheochromocytoma. N Engl J Med. 2002 346(19):1459-66. Wells SA Jr et al. Revised American Thyroid Association guidelines for the management of medullary thyroid carcinoma. Thyroid. 2015 Jun;25(6):567-610.
GeneDx RCV000182581 SCV000234933 pathogenic not provided 2018-09-07 criteria provided, single submitter clinical testing This pathogenic variant is denoted RET c.1900T>G at the cDNA level, p.Cys634Gly (C634G) at the protein level, and results in the change of a Cysteine to a Glycine (TGC>GGC). This variant has been reported in numerous individuals with pheochromocytoma and/or medullary thyroid cancer, and has been reported in association with multiple endocrine neoplasia 2A (MEN2A) (Mulligan 1993, McMahon 1994, Eng 1995, Landsvater 1996, Seri 1997, Hedayati 2011, Crona 2014, Lang 2015). Variants at codon Cysteine 634 occur in ~85% of families with MEN2A (Mulligan 1994, Mulligan 1995). RET Cys634Gly was not observed in large population cohorts (Lek 2016). This variant is located in the Cystein-rich domain of the extracellular domain (Garcia-Barcelo 2004). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, we consider this variant to be pathogenic.
Invitae RCV000654584 SCV000776478 pathogenic Multiple endocrine neoplasia, type 2 2018-11-06 criteria provided, single submitter clinical testing This sequence change replaces cysteine with glycine at codon 634 of the RET protein (p.Cys634Gly). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and glycine. This variant is not present in population databases (ExAC no frequency). This variant has been reported to segregate with multiple endocrine neoplasia type 2 in a single family and has been reported in many individuals with this condition or medullary thyroid carcinoma or pheochromcytomas (PMID: 12150334, 26356818, 9111993, 19201392 8099202, 12000816, 21765987, 26230854, 9950371). ClinVar contains an entry for this variant (Variation ID: 13908). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). Different missense substitutions at this codon (p.Cys634Arg, p.Cys634Tyr, p.Cys634Phe, p.Cys634Trp) has been determined to be pathogenic (PMID: 8103403, 21810974, 8099202, 7824936, 24716929, 16865647, 11939755, 24331334) and codon 634 is one of the most commonly altered codons in individuals affected with multiple endocrine neoplasia type 2 (PMID: 8918855, 26678667, 8099202, 12000816, 21765987). This suggests that the cysteine residue is critical for RET protein function and that other missense substitutions at this position may also be pathogenic. For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000014922 SCV000035178 pathogenic Multiple endocrine neoplasia, type 2a 2002-05-09 no assertion criteria provided literature only
OMIM RCV000014923 SCV000035179 pathogenic Pheochromocytoma 2002-05-09 no assertion criteria provided literature only
Research and Development, ARUP Laboratories RCV000654584 SCV000042488 pathogenic Multiple endocrine neoplasia, type 2 2018-05-04 no assertion criteria provided literature only Youngest with MTC: 3 yr. 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, and 18063059.

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