ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.9542T>G (p.Met3181Arg) (rs80359225)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000219030 SCV000275128 uncertain significance Hereditary cancer-predisposing syndrome 2015-04-16 criteria provided, single submitter clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000114131 SCV000147665 uncertain significance Breast-ovarian cancer, familial 2 2002-05-29 no assertion criteria provided clinical testing
GeneDx RCV000590128 SCV000210689 uncertain significance not provided 2018-08-30 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.9542T>G at the cDNA level, p.Met3181Arg (M3181R) at the protein level, and results in the change of a Methionine to an Arginine (ATG>AGG). Using alternate nomenclature, this variant would be defined BRCA2 9770T>G. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA2 Met3181Arg was not observed in large population cohorts (Lek 2016). Since Methionine and Arginine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA2 Met3181Arg is located in the DNA binding domain (Yang 2002). In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether BRCA2 Met3181Arg is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000590128 SCV000695250 uncertain significance not provided 2017-05-01 criteria provided, single submitter clinical testing Variant summary: The BRCA2 c.9542T>G (p.Met3181Arg) variant involves the alteration of a non-conserved nucleotide. 3/5 in silico tools predict a benign outcome for this variant. This variant is absent in 121376 control chromosomes. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. Karchin_ 2008 used protein likelihood ratio to predict variant as neutral. The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases/clinical diagnostic laboratories; nor evaluated for functional impact by in vivo/vitro studies. Because of the absence of clinical information and the lack of functional studies, the variant is classified as a variant of uncertain significance (VUS) until additional information becomes available.
Invitae RCV000045853 SCV000073866 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-11-30 criteria provided, single submitter clinical testing This sequence change replaces methionine with arginine at codon 3181 of the BRCA2 protein (p.Met3181Arg). The methionine residue is weakly conserved and there is a moderate physicochemical difference between methionine and arginine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with BRCA2-related disease. ClinVar contains an entry for this variant (Variation ID: 52867). 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: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). An algorithm developed specifically for the BRCA2 gene (PMID: 19043619) suggests that this missense change is likely to be tolerated. However, these predictions have not been confirmed by published functional studies. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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