ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.5075A>T (p.Asp1692Val) (rs397509222)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000048776 SCV000076789 uncertain significance Hereditary breast and ovarian cancer syndrome 2016-09-13 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with valine at codon 1692 of the BRCA1 protein (p.Asp1692Val). The aspartic acid residue is highly conserved and there is a large physicochemical difference between aspartic acid and valine. This variant is not present in population databases (rs397509222, ExAC no frequency). This variant has been reported in an individual affected with ovarian cancer (PMID: 21965345). ClinVar contains an entry for this variant (Variation ID: 55383). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may alter RNA splicing, but this prediction has not been confirmed by published transcriptional studies. In summary, this variant is a rare missense change with uncertain impact on mRNA splicing and protein function. While it is absent from the population and reported in an affected individual, the available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
GeneDx RCV000766432 SCV000567095 uncertain significance not provided 2015-07-09 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.5075A>T at the cDNA level and p.Asp1692Val (D1692V) at the protein level, and results in the change of an Aspartic Acid to a Valine (GAT>GTT). This variant, also known as BRCA1 5194A>T using alternate nomenclature, has been reported in one individual with ovarian cancer (Akbari 2011). BRCA1 Asp1692Val 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. BRCA1 Asp1692Val occurs at a position that is conserved in mammals and is located in the BRCT domain (UniProt). In silico analyses predict that this variant is probably damaging to protein structure and function. Despite some evidence suggesting pathogenicity, we consider BRCA1 Asp1692Val to be a variant of uncertain significance.
Ambry Genetics RCV000510122 SCV000608077 uncertain significance Hereditary cancer-predisposing syndrome 2015-09-16 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Rarity in general population databases (dbsnp, esp, 1000 genomes),Insufficient or conflicting evidence,Well-characterized mutation at same position
Sharing Clinical Reports Project (SCRP) RCV000238743 SCV000297618 uncertain significance Breast-ovarian cancer, familial 1 2011-12-05 no assertion criteria provided clinical testing
Research Molecular Genetics Laboratory,Women's College Hospital, University of Toronto RCV000486285 SCV000587457 uncertain significance not specified 2014-01-31 no assertion criteria provided research

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