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

gnomAD frequency: 0.00016  dbSNP: rs140214637

Total submissions: 8

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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000791415	SCV000288890	uncertain significance	not provided	2024-10-06	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). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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
Fulgent Genetics, Fulgent Genetics	RCV005031607	SCV005667306	uncertain significance	Fanconi anemia complementation group U; Spermatogenic failures 50; Premature ovarian failure 17	2024-02-16	criteria provided, single submitter	clinical testing
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.
PreventionGenetics, part of Exact Sciences	RCV003945051	SCV004771711	likely benign	XRCC2-related disorder	2021-01-08	no assertion criteria provided	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).