ClinVar Miner

Submissions for variant NM_000244.3(MEN1):c.737G>A (p.Cys246Tyr) (rs794728624)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000461795 SCV000541195 uncertain significance Multiple endocrine neoplasia, type 1 2016-11-15 criteria provided, single submitter clinical testing This sequence change replaces cysteine with tyrosine at codon 241 of the MEN1 protein (p.Cys241Tyr). 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 (ExAC no frequency). This variant has been reported in individuals affected with familial multiple endocrine neoplasia type 1 (PMID: 10576763, 17853334). ClinVar contains an entry for this variant (Variation ID: 200980). 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"). In summary, this variant is a rare missense change with uncertain impact on protein function. While it is absent from the population and reported in affected individuals, the available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics RCV000491344 SCV000579736 likely pathogenic Hereditary cancer-predisposing syndrome 2020-04-06 criteria provided, single submitter clinical testing The p.C241Y variant (also known as c.722G>A), located in coding exon 3 of the MEN1 gene, results from a G to A substitution at nucleotide position 722. The cysteine at codon 241 is replaced by tyrosine, an amino acid with highly dissimilar properties. This variant was detected in a familial MEN1 patient from Japan who had a personal history of parathyroid, pancreatic neuroendocrine, and adrenal tumors (Hai N et al. Eur. J. Endocrinol. 1999 Nov;141:475-80). In addition, two other alterations at the same codon, p.C241R and p.C241F, have also been detected MEN1 cohorts from the literature (Mutch MG et al. Hum. Mutat. 1999;13:175-85; Crépin M et al. Electrophoresis. 2003 Jan;24:26-33). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). 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 majority of available evidence to date, this variant is likely to be pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001285147 SCV001471539 likely pathogenic none provided 2020-02-12 criteria provided, single submitter clinical testing The MEN1 c.722G>A; p.Cys241Tyr variant (rs794728624) is reported in the literature in an individual with a clinical diagnosis of MEN1 (Hai 1999), and is reported in the ClinVar database (Variation ID: 200980). This variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The cysteine at codon 241 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Additionally, two other variants at this codon (Cys241Arg, Cys241Phe) are reported in individuals with MEN1 (Crepin 2003, Ellard 2005, Mutch 1999, see ClinVar Variation ID: 659647). Based on available information, the p.Cys241Tyr variant is considered to be likely pathogenic. REFERENCES Crepin M et al. Efficient mutation detection in MEN1 gene using a combination of single-strand conformation polymorphism (MDGA) and heteroduplex analysis. Electrophoresis. 2003 Jan;24(1-2):26-33. Ellard S et al. Detection of an MEN1 gene mutation depends on clinical features and supports current referral criteria for diagnostic molecular genetic testing. Clin Endocrinol (Oxf). 2005 Feb;62(2):169-75. Hai N et al. Germline MEN1 mutations in sixteen Japanese families with multiple endocrine neoplasia type 1 (MEN1). Eur J Endocrinol. 1999 Nov;141(5):475-80. Mutch MG et al. Germline mutations in the multiple endocrine neoplasia type 1 gene: evidence for frequent splicing defects. Hum Mutat. 1999;13(3):175-85.

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