ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.572T>A (p.Val191Asp) (rs80357142)

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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 RCV000164187 SCV000214807 likely benign Hereditary cancer-predisposing syndrome 2016-02-15 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Intact protein function observed in appropriate functional assay(s),Other data supporting benign classification
GeneDx RCV000481606 SCV000570480 uncertain significance not provided 2018-03-30 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.572T>A at the cDNA level, p.Val191Asp (V191D) at the protein level, and results in the change of a Valine to an Aspartic Acid (GTT>GAT). Using alternate nomenclature, this variant would be defined as BRCA1 691T>A. In vitro studies have shown this variant to be defective in single strand annealing repair and to have reduced expression levels (Towler 2013). BRCA1 Val191Asp was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located within a region known to interact with multiple other proteins (Paul 2014). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether BRCA1 Val191Asp is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Color RCV000164187 SCV000905043 likely benign Hereditary cancer-predisposing syndrome 2016-01-14 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000779902 SCV000916804 uncertain significance not specified 2018-09-25 criteria provided, single submitter clinical testing Variant summary: BRCA1 c.572T>A (p.Val191Asp) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.1e-06 in 246176 control chromosomes (gnomAD). To our knowledge, no occurrence of c.572T>A in individuals affected with Hereditary Breast and Ovarian Cancer has been reported. A functional study, Towler_2013, found the variant to act comparable to wild type in HDR activity. However, the SSA activity was significantly decreased (~40% of WT activity), although the protein expression was also reduced. Two ClinVar submission from clinical diagnostic laboratories (evaluation after 2014) cite the variant as uncertain significance and likely benign. Based on the evidence outlined above, the variant was classified as uncertain significance.
Breast Cancer Information Core (BIC) (BRCA1) RCV000112745 SCV000145631 uncertain significance Breast-ovarian cancer, familial 1 2002-05-29 no assertion criteria provided clinical testing

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