ClinVar Miner

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

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Total submissions: 6
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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 In silico models in agreement (benign);Other strong data supporting benign classification
GeneDx RCV000236937 SCV000292966 uncertain significance not provided 2021-02-03 criteria provided, single submitter clinical testing Observed in individuals with breast cancer (Oktay 2010); Not observed in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; Also known as 3366A>G; This variant is associated with the following publications: (PMID: 19996028, 28726806)
Invitae RCV000473151 SCV000549283 uncertain significance Hereditary breast and ovarian cancer syndrome 2020-06-20 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.
Color Health, Inc RCV000164419 SCV000904126 uncertain significance Hereditary cancer-predisposing syndrome 2019-04-30 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001526884 SCV001737623 uncertain significance not specified 2021-05-20 criteria provided, single submitter clinical testing Variant summary: BRCA1 c.3247A>G (p.Met1083Val) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 250484 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.3247A>G has been reported in the literature in individuals affected with Breast Cancer (e.g. Alkhalaf_2010, Oktay_2010, Dorling_2021). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance and one ClinVar submitter (evaluation after 2014) cites it as likely benign. Based on the evidence outlined above, the variant was classified as uncertain significance.
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001353671 SCV000591432 uncertain significance Malignant tumor of breast no assertion criteria provided clinical testing The BRCA1, p.Met1083Val variant was not identified in the literature and was identified only in the ClinVar database (classified as an unclassified variant by the Ambry Genetics).The p.Met1083 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein. However, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and 1 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of unknown significance.

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