ClinVar Miner

Submissions for variant NM_000059.4(BRCA2):c.7A>G (p.Ile3Val)

gnomAD frequency: 0.00001  dbSNP: rs770479195
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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000222062 SCV000275326 uncertain significance Hereditary cancer-predisposing syndrome 2020-12-02 criteria provided, single submitter clinical testing The p.I3V variant (also known as c.7A>G), located in coding exon 1 of the BRCA2 gene, results from an A to G substitution at nucleotide position 7. The isoleucine at codon 3 is replaced by valine, an amino acid with highly similar properties. This amino acid position is poorly conserved in available vertebrate species, and valine is the reference amino acid in multiple 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.
Invitae RCV000536609 SCV000635628 uncertain significance Hereditary breast ovarian cancer syndrome 2024-01-15 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 3 of the BRCA2 protein (p.Ile3Val). This variant is present in population databases (rs770479195, gnomAD 0.0009%). This missense change has been observed in individual(s) with breast cancer (PMID: 21520333, 35264596; Invitae). ClinVar contains an entry for this variant (Variation ID: 231466). 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 BRCA2 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.
Mendelics RCV000536609 SCV000838717 uncertain significance Hereditary breast ovarian cancer syndrome 2018-07-02 criteria provided, single submitter clinical testing
Color Diagnostics, LLC DBA Color Health RCV000222062 SCV000911731 uncertain significance Hereditary cancer-predisposing syndrome 2023-11-16 criteria provided, single submitter clinical testing This missense variant replaces isoleucine with valine at codon 3 of the BRCA2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 2/251358 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000985596 SCV001133920 uncertain significance not provided 2019-07-28 criteria provided, single submitter clinical testing
Mendelics RCV000988978 SCV001138936 uncertain significance Breast-ovarian cancer, familial, susceptibility to, 2 2019-05-28 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001193318 SCV001362069 uncertain significance not specified 2019-10-04 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.7A>G (p.Ile3Val) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251358 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.7A>G has been reported in the literature in validation studies with limited available information (Mattocks_2010, van der Hout_2006). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four ClinVar submissions (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
GeneDx RCV000985596 SCV002005884 uncertain significance not provided 2019-08-20 criteria provided, single submitter clinical testing Not observed at a significant frequency in large population cohorts (Lek et al., 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 BRCA2 235A>G; This variant is associated with the following publications: (PMID: 20167696)
Sema4, Sema4 RCV000222062 SCV002531901 uncertain significance Hereditary cancer-predisposing syndrome 2022-03-17 criteria provided, single submitter curation

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