ClinVar Miner

Submissions for variant NM_005431.2(XRCC2):c.714G>C (p.Arg238Ser) (rs534746330)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000227344 SCV000288894 uncertain significance not specified 2016-01-22 criteria provided, single submitter clinical testing This sequence change replaces arginine with serine at codon 238 of the XRCC2 protein (p.Arg238Ser). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and serine. This variant is present in population databases (rs534746330, ExAC 0.009%). This variant has been reported in the literature in an individual affected with breast cancer (PMID:23054243). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies. In summary, this is a rare missense change with uncertain impact on protein function. This variant has been reported in both the population and an affected individual, but the available evidence is insufficient at this time to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
GeneDx RCV000657150 SCV000572000 uncertain significance not provided 2017-12-11 criteria provided, single submitter clinical testing This variant is denoted XRCC2 c.714G>C at the cDNA level, p.Arg238Ser (R238S) at the protein level, and results in the change of an Arginine to a Serine (AGG>AGC). This variant has been reported in at least one individual with breast cancer, and in XRCC2-deficient hamster cells was able to restore RAD51C foci formation to 77% of wild-type (Hilbers 2012, Hilbers 2016). XRCC2 Arg238Ser was not observed at a significant allele frequency in large population cohorts (Lek 2016). Since Arginine and Serine differ in some properties, this is considered a semi-conservative amino acid substitution. XRCC2 Arg238Ser is not located in a known functional domain. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Based on currently available evidence, it is unclear whether XRCC2 Arg238Ser is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Mendelics RCV000709047 SCV000838281 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-02 criteria provided, single submitter clinical testing
Mendelics RCV000988011 SCV001137557 uncertain significance Fanconi anemia, complementation group U 2019-05-28 criteria provided, single submitter clinical testing
Leiden Open Variation Database RCV000657150 SCV001364740 uncertain significance not provided 2016-04-14 no assertion criteria provided curation Curator: Arleen D. Auerbach. Submitter to LOVD: Florentine Hilbers.

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