ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.734A>T (p.Asp245Val) (rs80356865)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000129392 SCV000184158 uncertain significance Hereditary cancer-predisposing syndrome 2018-04-30 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Breast Cancer Information Core (BIC) (BRCA1) RCV000112778 SCV000145672 uncertain significance Breast-ovarian cancer, familial 1 2002-06-20 no assertion criteria provided clinical testing
Counsyl RCV000112778 SCV000488015 uncertain significance Breast-ovarian cancer, familial 1 2015-12-16 criteria provided, single submitter clinical testing
Department of Medical Genetics,University Hospital of North Norway RCV000112778 SCV000301429 uncertain significance Breast-ovarian cancer, familial 1 2016-05-01 no assertion criteria provided clinical testing
GeneDx RCV000766561 SCV000210086 uncertain significance not provided 2014-06-25 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.734A>T at the cDNA level, p.Asp245Val (D245V) at the protein level, and results in the change of an Aspartic Acid to a Valine (GAT>GTT). BRCA1 Asp245Val performed similarly to wildtype in a functional growth assay in BRCA1-deficient mouse embryonic stem cells (Bouwman 2013). BRCA1 Asp245Val was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating 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 Asp245Val occurs at a position that is well conserved across species and is not located in a known functional domain (UniProt). In addition, in silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available information, it is unclear whether BRCA1 Asp245Val is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae RCV000049112 SCV000077125 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-07-10 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with valine at codon 245 of the BRCA1 protein (p.Asp245Val). The aspartic acid residue is moderately conserved and there is a large physicochemical difference between aspartic acid and valine. This variant is present in population databases (rs80356865, ExAC <0.01%). This variant has been reported in an individual affected with breast and/or ovarian cancer (PMID: 26843898). ClinVar contains an entry for this variant (Variation ID: 55682) Experimental studies have shown that this variant can functionally complement BRCA1-deficient mouse embryonic stem cells, suggesting that this variant does not have a functional impact on BRCA1 protein (PMID: 23867111). 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.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000212161 SCV000600436 uncertain significance not specified 2016-08-31 criteria provided, single submitter clinical testing

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