ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.572A>T (p.Asp191Val) (rs397507798)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000129294 SCV000184055 uncertain significance Hereditary cancer-predisposing syndrome 2016-09-20 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Other data supporting pathogenic classification,In silico models in agreement (deleterious) and/or completely conserved position in appropriate species,Insufficient or conflicting evidence,Deficient protein function in appropriate functional assay(s)
Counsyl RCV000411982 SCV000487785 uncertain significance Breast-ovarian cancer, familial 2 2015-11-17 criteria provided, single submitter clinical testing
GeneDx RCV000486563 SCV000568449 uncertain significance not provided 2016-09-28 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.572A>T at the cDNA level, p.Asp191Val (D191V) at the protein level, and results in the change of an Aspartic Acid to a Valine (GAT>GTT). This variant, previously published as BRCA2 800A>T, was identified in at least two individuals with a personal and/or family history of breast cancer (Balia 2011). Balia et al. (2011) showed that this variant lead to an increased rate of homologous recombination, when compared to wild-type; however, tumor analysis revealed no loss of heterozygosity. While skipping of BRCA2 exon 7 is a naturally occurring isoform, BRCA2 Asp191Val has been shown to mildly increase this exon skipping compared to wild-type (Di Giacomo 2013). BRCA2 Asp191Val was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Aspartic Acid and Valine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA2 Asp191Val occurs at a position where amino acids with properties similar to Aspartic Acid are tolerated across species and is not located in a known functional domain (UniProt). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether BRCA2 Asp191Val is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.

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