Submissions for variant NM_005431.2(XRCC2):c.596T>C (p.Met199Thr)

gnomAD frequency: 0.00002  dbSNP: rs149099078

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000767011	SCV000211843	uncertain significance	not provided	2016-09-02	criteria provided, single submitter	clinical testing	This variant is denoted XRCC2 c.596T>C at the cDNA level, p.Met199Thr (M199T) at the protein level, and results in the change of a Methionine to a Threonine (ATG>ACG). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. XRCC2 Met199Thr was not observed at a significant allele frequency in the 1000 Genomes Project. Since Methionine and Threonine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. XRCC2 Met199Thr occurs at a position where amino acids with properties similar to Methionine are tolerated across species and is located within the ATPase domain (Kim 2011). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available information, it is unclear whether XRCC2 Met199Thr is pathogenic or benign. We consider it to be a variant of uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000767011	SCV000550363	uncertain significance	not provided	2025-01-20	criteria provided, single submitter	clinical testing	This sequence change replaces methionine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 199 of the XRCC2 protein (p.Met199Thr). This variant is present in population databases (rs149099078, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. 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: 182996). 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) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on 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.
Fulgent Genetics, Fulgent Genetics	RCV000765951	SCV000897372	uncertain significance	Fanconi anemia complementation group U	2018-10-31	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV001024734	SCV001186805	likely benign	Hereditary cancer-predisposing syndrome	2021-12-21	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.
Genetic Services Laboratory, University of Chicago	RCV001818361	SCV002071787	uncertain significance	not specified	2021-08-04	criteria provided, single submitter	clinical testing	DNA sequence analysis of the XRCC2 gene demonstrated a sequence change, c.596T>C, in exon 3 that results in an amino acid change, p.Met199Thr. This sequence change has been described in the gnomAD database with a frequency of 0.09% in the East Asian subpopulation (dbSNP rs149099078). The p.Met199Thr change affects a highly conserved amino acid residue located in a domain of the XRCC2 protein that is known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Met199Thr substitution. This sequence change does not appear to have been previously described in individuals with XRCC2-related disorders. Due to insufficient evidences and the lack of functional studies, the clinical significance of the p.Met199Thr change remains unknown at this time.
Sema4, Sema4	RCV001024734	SCV002538378	uncertain significance	Hereditary cancer-predisposing syndrome	2021-07-22	criteria provided, single submitter	curation
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000767011	SCV004221590	likely benign	not provided	2023-06-23	criteria provided, single submitter	clinical testing