ClinVar Miner

Submissions for variant NM_020975.6(RET):c.1901G>A (p.Cys634Tyr) (rs75996173)

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Total submissions: 20
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000014924 SCV000053074 pathogenic Multiple endocrine neoplasia, type 2a 2019-07-18 criteria provided, single submitter clinical testing Variant summary: RET c.1901G>A (p.Cys634Tyr) results in a non-conservative amino acid change located in the extracellular domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 247574 control chromosomes. c.1901G>A has been well reported in the literature in multiple individuals affected with Multiple Endocrine Neoplasia Type 2A (example Chiefari_1998, Frank-Raue_2006). These data indicate that the variant is strongly associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function demonstrating a gain of function mechanism due to activation of the RET proto-oncogene (example Santoro_1995). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Ambry Genetics RCV000129490 SCV000184262 pathogenic Hereditary cancer-predisposing syndrome 2019-04-25 criteria provided, single submitter clinical testing The p.C634Y pathogenic mutation (also known as c.1901G>A) is located in coding exon 11 of the RET gene. This alteration results from a G to A substitution at nucleotide position 1901. The cysteine at codon 634 is replaced by tyrosine, an amino acid with highly dissimilar properties. The p.C634Y mutation has been reported in several unrelated families diagnosed with MEN2A and/or familial medullary thyroid carcinoma (FMTC) (Mulligan et al. Nature. 1993;363:458-460; Marsh DJ et al. Genomics. 1994;23(2):477-479; Hedayati et al. J Thyroid Res. 2011;2011:264248; Sriphrapradang C et al. Clin Med Insights Endocrinol Diabetes. 2017 Apr;10:1179551417705122). Amino acid position 634 is a well described mutation hot spot associated with MEN2A/FMTC. Studies evaluating genotype-phenotype correlation suggest higher penetrance for pheochromocytoma in MEN2 patients with mutations at amino acid position 634 (Neumann HP et al. N. Engl. J. Med. 2002;346:1459-66, Quayle FJ et al. Surgery 2007;142:800-5; Yip L et al. Arch Surg 2003;138:409-16). Revised American Thyroid Association Guidelines categorize the p.C634Y alteration as high risk (ATA-H) and recommend surveillance and prophylactic surgery in early childhood (Wells SA et al. Thyroid 2015 Jun;25(6):567-610). Of note, this alteration has been referred to as p.C380Y (c.1832G>A) and p.C634Y (c.2096G>A) in the published literature. Based on the available evidence, p.C634Y is classified as a pathogenic mutation.
GeneDx RCV000182582 SCV000234934 pathogenic not provided 2018-10-03 criteria provided, single submitter clinical testing This pathogenic variant is denoted RET c.1901G>A at the cDNA level, p.Cys634Tyr (C634Y) at the protein level, and results in the change of a Cysteine to a Tyrosine (TGC>TAC). This variant, also published as RET Cys380Tyr, has been observed in numerous individuals with features of MEN2A, including diagnoses of medullary thyroid cancer (MTC), pheochromocytoma and parathyroid disease, and segregates with disease in multiple families (Fink 1996, Frank-Raue 1996, Elisei 2007, Valdes 2015, Aghdam 2016). Variants at codon Cysteine 634 occur in ~85% of families with MEN2A (Mulligan 1994, Mulligan 1995). Furthermore, functional assays demonstrate that this variant converts RET into a dominant transforming gene (Santoro 1995). RET Cys634Tyr was not observed in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Cysteine and Tyrosine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. RET Cys634Tyr occurs at a position that is conserved across species and is located in the extracellular cysteine-rich domain (Garcia-Barcelo 2004). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, we consider this variant to be pathogenic.
Invitae RCV000476408 SCV000543790 pathogenic Multiple endocrine neoplasia, type 2 2018-12-05 criteria provided, single submitter clinical testing This sequence change replaces cysteine with tyrosine at codon 634 of the RET protein (p.Cys634Tyr). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and tyrosine. This variant is not present in population databases (rs75996173, ExAC no frequency). This variant has been reported to segregate in families affected with multiple endocrine neoplasia type 2A and medullary thyroid cancer (PMID: 8099202, 23723040, 2008030). This variant has also been reported in individuals affected with pheochromocytoma (PMID: 12000816). ClinVar contains an entry for this variant (Variation ID: 13909). This variant affects one of the most commonly mutated codons in the RET gene in individuals affected with multiple endocrine neoplasia type 2 (PMID: 8099202, 12000816, 21765987) Experimental studies have showed that this variant has an activating effect on the RET protein (PMID: 7824936). For these reasons, this variant has been classified as Pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000507297 SCV000605016 pathogenic not specified 2016-08-15 criteria provided, single submitter clinical testing
Center for Human Genetics, Inc,Center for Human Genetics, Inc RCV000014924 SCV000782257 pathogenic Multiple endocrine neoplasia, type 2a 2016-11-01 criteria provided, single submitter clinical testing
Counsyl RCV000014924 SCV000785514 pathogenic Multiple endocrine neoplasia, type 2a 2017-08-30 criteria provided, single submitter clinical testing
Athena Diagnostics Inc RCV000182582 SCV000842752 pathogenic not provided 2021-05-14 criteria provided, single submitter clinical testing The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). This variant has been identified in multiple unrelated individuals with clinical features associated with this gene. At least one other missense variant at this codon is considered to be pathogenic or likely pathogenic, suggesting this variant may also cause disease. The American Thyroid Association has placed this variant into the ATA-H category, formerly known as level C, for having a high risk of developing aggressive medullary thyroid carcinoma (MTC; see PMID: 25810047). This variant segregates with disease in multiple families. Computational tools predict that this variant is damaging.
Suma Genomics RCV000425364 SCV001847694 pathogenic Multiple endocrine neoplasia, type 2b criteria provided, single submitter clinical testing
OMIM RCV000014924 SCV000035180 pathogenic Multiple endocrine neoplasia, type 2a 2002-05-09 no assertion criteria provided literature only
OMIM RCV000014925 SCV000035181 pathogenic Pheochromocytoma 2002-05-09 no assertion criteria provided literature only
Research and Development, ARUP Laboratories RCV000476408 SCV000055373 pathogenic Multiple endocrine neoplasia, type 2 2018-05-04 no assertion criteria provided literature only MEN2A or FMTC families. Youngest with MTC: 10 months. Youngest with Pheo: 8 yr. Youngest with 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 c.1893C>A(;)1901G>A, c.[1901G>A; 2121T>A], c.[1901G>A;2556C>G], and c.[1901G>A;c.2372A>T].
Database of Curated Mutations (DoCM) RCV000421191 SCV000505641 likely pathogenic Neoplasm 2015-07-14 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000438527 SCV000510492 likely pathogenic Medullary thyroid carcinoma 2016-05-13 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000422622 SCV000510493 likely pathogenic Multiple endocrine neoplasia, type 1 2016-05-13 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000432822 SCV000510494 likely pathogenic Multiple endocrine neoplasia, type 4 2016-05-13 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000014924 SCV000510495 likely pathogenic Multiple endocrine neoplasia, type 2a 2016-05-13 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000425364 SCV000510496 likely pathogenic Multiple endocrine neoplasia, type 2b 2016-05-13 no assertion criteria provided literature only
Genome Diagnostics Laboratory, University Medical Center Utrecht RCV000182582 SCV001926394 pathogenic not provided no assertion criteria provided clinical testing
Human Genetics - Radboudumc,Radboudumc RCV000182582 SCV001958702 pathogenic not provided no assertion criteria provided clinical testing

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