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

Total submissions: 5

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 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.