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

dbSNP: rs75076352

Total submissions: 10

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	2023-12-05	criteria provided, single submitter	clinical testing	This sequence change replaces cysteine, which is neutral and slightly polar, with glycine, which is neutral and non-polar, at codon 634 of the RET protein (p.Cys634Gly). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with medullary thyroid carcinoma or pheochromcytomas and multiple endocrine neoplasia type 2 (PMID: 8099202, 9111993, 9950371, 12000816, 12150334, 19201392, 21765987, 26230854, 26356818). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 13908). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. This variant disrupts the p.Cys634 amino acid residue in RET. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7824936, 8099202, 8103403, 8918855, 11939755, 12000816, 16865647, 21765987, 21810974, 24331334, 24716929, 26678667). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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	2023-03-03	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; Algün 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). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is pathogenic for MEN2; however, the association of this alteration with Hirschsprung disease is unknown.
Clinical Genetics and Genomics, 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