ClinVar Miner

Submissions for variant NM_000059.4(BRCA2):c.1462A>G (p.Ile488Val)

gnomAD frequency: 0.00001  dbSNP: rs864622352
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory of Molecular Diagnosis of Cancer, West China Hospital, Sichuan University RCV000240763 SCV000265931 uncertain significance Breast neoplasm 2015-11-01 criteria provided, single submitter research
Ambry Genetics RCV000572755 SCV000665085 likely benign Hereditary cancer-predisposing syndrome 2017-11-28 criteria provided, single submitter clinical testing This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Color Diagnostics, LLC DBA Color Health RCV000572755 SCV000913979 uncertain significance Hereditary cancer-predisposing syndrome 2019-06-11 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV001239569 SCV001412452 uncertain significance Hereditary breast ovarian cancer syndrome 2023-10-05 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 488 of the BRCA2 protein (p.Ile488Val). This variant is present in population databases (no rsID available, gnomAD 0.004%). This missense change has been observed in individual(s) with breast cancer (PMID: 27257965). ClinVar contains an entry for this variant (Variation ID: 224457). 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. 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.
University of Washington Department of Laboratory Medicine, University of Washington RCV000572755 SCV003851407 likely benign Hereditary cancer-predisposing syndrome 2023-03-23 criteria provided, single submitter curation Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673).
St. Jude Molecular Pathology, St. Jude Children's Research Hospital RCV003444220 SCV004171487 uncertain significance Breast-ovarian cancer, familial, susceptibility to, 2 2023-10-18 criteria provided, single submitter clinical testing The BRCA2 c.1462A>G (p.Ile488Val) missense change has a maximum founder subpopulation frequency of 0.004% and a maximum non-founder subpopulation frequency of 0.0007% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org). The in silico tool REVEL is inconclusive about a pathogenic or benign effect of this variant on protein function, and to our knowledge functional studies have not been performed. This variant has been reported in individuals with breast cancer (PMID: 27257965, 30400234). To our knowledge, this variant has not been reported in individuals with Fanconi anemia. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance.

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