ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.889A>G (p.Met297Val) (rs80357196)

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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 RCV000131947 SCV000187004 uncertain significance Hereditary cancer-predisposing syndrome 2014-04-24 criteria provided, single submitter clinical testing
GeneDx RCV000486631 SCV000565727 uncertain significance not provided 2016-09-15 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.889A>G at the cDNA level, p.Met297Val (M297V) at the protein level, and results in the change of a Methionine to a Valine (ATG>GTG). Using alternate nomenclature, this variant would be defined as BRCA1 1008A>G. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA1 Met297Val 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 Methionine and Valine share similar properties, this is considered a conservative amino acid substitution. BRCA1 Met297Val occurs at a position where amino acids with properties similar to Methionine are tolerated across species and is located in a region known to interact with multiple proteins (Paul 2014). 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 Met297Val is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000549625 SCV000636082 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-06-14 criteria provided, single submitter clinical testing This sequence change replaces methionine with valine at codon 297 of the BRCA1 protein (p.Met297Val). The methionine residue is moderately conserved and there is a small physicochemical difference between methionine and valine. 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: 142628). 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 tolerated, 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.
Counsyl RCV000239288 SCV000785223 uncertain significance Breast-ovarian cancer, familial 1 2017-06-08 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000239288 SCV000297626 uncertain significance Breast-ovarian cancer, familial 1 2011-12-21 no assertion criteria provided clinical testing

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