ClinVar Miner

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

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000182581 SCV000234933 pathogenic not provided 2021-04-21 criteria provided, single submitter clinical testing Not observed in large population cohorts (Lek 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 24466223, 26267327, 30763276, 27349013, 28605116, 7907913, 12000816, 26071011, 8825918, 23416954, 9467562, 8981969, 12788868, 9174404, 18063059, 19201392, 9111993, 26758973, 28946813, 27864651, 29420094, 31510104, 19258401, 12150334, 18062802, 30392857, 8099202, 7915166, 7595170, 8557249, 21765987, 14633923)
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.
Invitae RCV000654584 SCV000776478 pathogenic Multiple endocrine neoplasia, type 2 2020-08-31 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.
Athena Diagnostics Inc RCV000182581 SCV001144498 pathogenic not provided 2018-12-05 criteria provided, single submitter clinical testing Located at a critical residue of the protein. Not found in the total gnomAD dataset, and the data is high quality (0/278388 chr). Found in at least one symptomatic patient. Predicted to have a damaging effect on the protein. Other pathogenic or likely pathogenic variants affect the same amino acid. Damaging to protein function(s) relevant to disease mechanism. Co-segregation with disease is reported.
Ambry Genetics RCV001013616 SCV001174224 pathogenic Hereditary cancer-predisposing syndrome 2019-03-28 criteria provided, single submitter clinical testing The p.C634G pathogenic mutation (also known as c.1900T>G), located in coding exon 11 of the RET gene, results from a T to G substitution at nucleotide position 1900. The cysteine at codon 634 is replaced by glycine, an amino acid with highly dissimilar properties. Amino acid position 634 is a well described mutation hot spot associated with Multiple Endocrine Neoplasia Type 2A (MEN2A) and Familial Medullary Thyroid Carcinoma (FMTC). This mutation has been reported in multiple MEN2A/FMTC families (Mulligan LM et al. Nature. 1993 Jun;363:458-60; Mulligan LM et al. Nat. Genet. 1994 Jan;6:70-4; McMahon R et al. Hum. Mol. Genet. 1994 Apr;3:643-6; Marsh DJ et al. Genomics. 1994 Sep;23:477-9; Mulligan LM et al. J. Intern. Med. 1995 Oct;238:343-6; Eng C et al. JAMA. 1996 Nov;276:1575-9). It has also been reported in individuals with MEN2A and Cutaneous Lichen Amyloidosis (Seri M et al. Clin. Genet. 1997 Feb;51:86-90; Scapineli JO et al. Fam. Cancer. 2016 10;15:625-33). Additionally, this mutation has been identified in multiple individuals with a history of pheochromocytoma (Seri M et al. Clin. Genet. 1997 Feb;51:86-90; Neumann HP et al. N. Engl. J. Med. 2002 May;346:1459-66; Alg&uuml;n E et al. J. Endocrinol. Invest. 2002 Jul-Aug;25:603-8; Amar L et al. J. Clin. Oncol. 2005 Dec;23:8812-8). The American Thyroid Association categorizes this mutation as high risk (ATA-H) and recommends surveillance, screening, and/or possible surgical interventions in early childhood (American Thyroid Association Guidelines Task Force. Thyroid. 2009 Jun;19:565-612; Wells SA et al. Thyroid. 2015 Jun;25:567-610)<span style="font-size:12px"><span style="color:rgb(0, 0, 0); font-family:arial,helvetica,clean,sans-serif">. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Clinical Genetics Karolinska University Hospital,Karolinska University Hospital RCV000182581 SCV001449636 pathogenic not provided 2016-04-15 criteria provided, single submitter clinical testing
Department of Molecular Diagnostics, Institute of Oncology Ljubljana RCV001310209 SCV001499814 pathogenic Familial medullary thyroid carcinoma 2020-04-02 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001420921 SCV001623374 pathogenic MEN2 phenotype: Unclassified 2021-04-25 criteria provided, single submitter clinical testing Variant summary: RET c.1900T>G (p.Cys634Gly) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The most frequent mutations in the RET proto-oncogene have been found in five cysteine codons 609, 611, 618, and 620 of exon 10 and codon 634 of exon 11. The variant was absent in 247534 control chromosomes. c.1900T>G has been widely reported in the literature in multiple individuals affected with Multiple Endocrine Neoplasia Type 2/Phaeochromocytoma/Medullary Carcinoma of the Thyroid/ multiple endocrine neoplasia type 2A (MEN 2A)-cutaneous lichen amyloidosis (example, Mulligan_1993, Neumann_2002, Sanz_2009, Hedayati_2011, Qi_2018, Maciel_2019). These data indicate that the variant is very likely to be associated with disease. Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was 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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