ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.5429T>C (p.Val1810Ala) (rs80357451)

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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 RCV000165514 SCV000216246 uncertain significance Hereditary cancer-predisposing syndrome 2017-10-17 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
GeneDx RCV000759560 SCV000293736 uncertain significance not provided 2015-12-21 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.5429T>C at the cDNA level, p.Val1810Ala (V1810A) at the protein level, and results in the change of a Valine to an Alanine (GTG>GCG). Using alternate nomenclature, this variant would be defined as BRCA1 5548T>C. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA1 Val1810Ala 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 Valine and Alanine share similar properties, this is considered a conservative amino acid substitution. BRCA1 Val1810Ala occurs at a position where amino acids with properties similar to Valine are tolerated across species and is located in the BRCT2 domain in a region known to interact with multiple proteins (Paul 2014, Uniprot). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, it is unclear whether BRCA1 Val1810Ala is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000500971 SCV000636040 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-11-19 criteria provided, single submitter clinical testing This sequence change replaces valine with alanine at codon 1810 of the BRCA1 protein (p.Val1810Ala). The valine residue is highly conserved and there is a small physicochemical difference between valine and alanine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with BRCA1-related disease. ClinVar contains an entry for this variant (Variation ID: 185996). 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 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 RCV000165514 SCV000683315 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-28 criteria provided, single submitter clinical testing
Counsyl RCV000662954 SCV000785920 uncertain significance Breast-ovarian cancer, familial 1 2018-01-10 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000759560 SCV000888947 uncertain significance not provided 2017-10-25 criteria provided, single submitter clinical testing

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