ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.646A>G (p.Ile216Val)

dbSNP: rs398122704
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000232412 SCV000289836 uncertain significance Hereditary breast ovarian cancer syndrome 2023-11-14 criteria provided, single submitter clinical testing This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 216 of the BRCA1 protein (p.Ile216Val). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with BRCA1-related conditions. ClinVar contains an entry for this variant (Variation ID: 91659). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt BRCA1 protein function with a negative predictive value of 95%. 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.
Ambry Genetics RCV000562887 SCV000665885 uncertain significance Hereditary cancer-predisposing syndrome 2022-08-04 criteria provided, single submitter clinical testing The p.I216V variant (also known as c.646A>G), located in coding exon 8 of the BRCA1 gene, results from an A to G substitution at nucleotide position 646. The isoleucine at codon 216 is replaced by valine, an amino acid with highly similar properties. This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
GeneDx RCV001588901 SCV001814702 uncertain significance not provided 2019-06-07 criteria provided, single submitter clinical testing Not observed in large population cohorts (Lek 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; Also known as 765A>G
Sharing Clinical Reports Project (SCRP) RCV000077176 SCV000108973 uncertain significance Breast-ovarian cancer, familial, susceptibility to, 1 2012-04-02 no assertion criteria provided clinical testing

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