Submissions for variant NM_005431.2(XRCC2):c.613T>G (p.Ser205Ala)

gnomAD frequency: 0.00017  dbSNP: rs56103026

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000161109	SCV000211844	uncertain significance	not specified	2017-03-21	criteria provided, single submitter	clinical testing	This variant is denoted XRCC2 c.613T>G at the cDNA level, p.Ser205Ala (S205A) at the protein level, and results in the change of a Serine to an Alanine (TCA>GCA). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. XRCC2 Ser205Ala was not observed at a significant allele frequency in the NHLBI Exome Sequencing Project. Since Serine and Alanine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. XRCC2 Ser205Ala occurs at a position that is not conserved and is located in the ATPase domain (Kim 2011). In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available evidence, it is unclear whether XRCC2 Ser205Ala is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Eurofins Ntd Llc (ga)	RCV000726016	SCV000341255	uncertain significance	not provided	2016-04-29	criteria provided, single submitter	clinical testing
Mendelics	RCV001024935	SCV000838287	uncertain significance	Hereditary cancer-predisposing syndrome	2018-07-02	criteria provided, single submitter	clinical testing
Invitae	RCV000726016	SCV000942467	uncertain significance	not provided	2023-10-19	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 205 of the XRCC2 protein (p.Ser205Ala). This variant is present in population databases (rs56103026, gnomAD 0.05%). This variant has not been reported in the literature in individuals affected with XRCC2-related conditions. ClinVar contains an entry for this variant (Variation ID: 182997). 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. 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.
Mendelics	RCV000988015	SCV001137562	uncertain significance	Fanconi anemia complementation group U	2019-05-28	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV001024935	SCV001187033	uncertain significance	Hereditary cancer-predisposing syndrome	2021-12-15	criteria provided, single submitter	clinical testing	The p.S205A variant (also known as c.613T>G), located in coding exon 3 of the XRCC2 gene, results from a T to G substitution at nucleotide position 613. The serine at codon 205 is replaced by alanine, an amino acid with similar properties. This alteration has been reported in a cohort of African-American women with breast cancer (Ding YC et al. Fam Cancer, 2018 04;17:187-195). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000726016	SCV004221592	likely benign	not provided	2022-10-09	criteria provided, single submitter	clinical testing