ClinVar Miner

Submissions for variant NM_005431.2(XRCC2):c.283A>G (p.Ile95Val)

gnomAD frequency: 0.00016  dbSNP: rs140214637
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000115888 SCV000149797 likely benign not specified 2017-10-09 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Invitae RCV000791415 SCV000288890 uncertain significance not provided 2024-01-25 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 95 of the XRCC2 protein (p.Ile95Val). This variant is present in population databases (rs140214637, gnomAD 0.05%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with breast cancer, ovarian cancer, and pancreatic cancer (PMID: 22464251, 23054243, 26689913, 28767289). ClinVar contains an entry for this variant (Variation ID: 127954). 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 XRCC2 protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change does not substantially affect XRCC2 function (PMID: 27233470). 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 RCV000570999 SCV000675837 likely benign Hereditary cancer-predisposing syndrome 2018-11-02 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.
Mendelics RCV000988018 SCV001137565 uncertain significance Fanconi anemia complementation group U 2019-05-28 criteria provided, single submitter clinical testing
Sema4, Sema4 RCV000570999 SCV002538368 likely benign Hereditary cancer-predisposing syndrome 2020-12-17 criteria provided, single submitter curation
PreventionGenetics, part of Exact Sciences RCV003945051 SCV004771711 likely benign XRCC2-related disorder 2021-01-08 criteria provided, single submitter clinical testing This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
Leiden Open Variation Database RCV000791415 SCV001364752 uncertain significance not provided 2012-05-02 no assertion criteria provided curation Curator: Arleen D. Auerbach. Submitter to LOVD: Johan den Dunnen.

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