ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.3247A>G (p.Met1083Val) (rs397507213)

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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 RCV000164419 SCV000215058 likely benign Hereditary cancer-predisposing syndrome 2018-11-28 criteria provided, single submitter clinical testing Other strong data supporting benign classification;In silico models in agreement (benign)
GeneDx RCV000236937 SCV000292966 uncertain significance not provided 2018-02-21 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.3247A>G at the cDNA level, p.Met1083Val (M1083V) at the protein level, and results in the change of a Methionine to a Valine (ATG>GTG). This variant, also published as BRCA1 3366A>G using alternate nomenclature, has been reported in at least one individual with a history of early-onset breast cancer (Oktay 2010). BRCA1 Met1083Val was not observed in large population cohorts (Lek 2016). This variant is not located in a known functional domain. 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 BRCA1 Met1083Val is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000473151 SCV000549283 uncertain significance Hereditary breast and ovarian cancer syndrome 2019-08-22 criteria provided, single submitter clinical testing This sequence change replaces methionine with valine at codon 1083 of the BRCA1 protein (p.Met1083Val). The methionine residue is weakly conserved and there is a small physicochemical difference between methionine and valine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in an individual who was screened for hereditary breast and ovarian cancer (PMID: 18092194). It was also found in an individual with breast cancer who underwent oocyte or embryo cryopreservation for fertility preservation (PMID: 19996028). This variant is also known as 3366A>G in the literature. ClinVar contains an entry for this variant (Variation ID: 185061). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The valine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000473151 SCV000591432 uncertain significance Hereditary breast and ovarian cancer syndrome 2015-03-27 criteria provided, single submitter clinical testing
Color RCV000164419 SCV000904126 uncertain significance Hereditary cancer-predisposing syndrome 2019-04-30 criteria provided, single submitter clinical testing

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