Submissions for variant NM_005431.2(XRCC2):c.271C>T (p.Arg91Trp)

gnomAD frequency: 0.00004  dbSNP: rs730882043

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000161106	SCV000211841	uncertain significance	not provided	2016-10-31	criteria provided, single submitter	clinical testing	This variant is denoted XRCC2 c.271C>T at the cDNA level, p.Arg91Trp (R91W) at the protein level, and results in the change of an Arginine to a Tryptophan (CGG>TGG). This variant has been observed in breast cancer families; however, in one family it did not completely segregate with cancer (Park 2012). This variant was observed in a homologous repair assay to have a moderate effect on XRCC2 function and only partially rescued RAD51 foci formation (Hilbers 2016). XRCC2 Arg91Trp was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Arginine and Tryptophan differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. XRCC2 Arg91Trp occurs at a position that is conserved across species and is not located in a known functional domain (O'Regan 2001, Miller 2004). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available information, it is unclear whether XRCC2 Arg91Trp is pathogenic or benign. We consider it to be a variant of uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000161106	SCV000945407	uncertain significance	not provided	2024-05-08	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 91 of the XRCC2 protein (p.Arg91Trp). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with breast cancer (PMID: 22464251). ClinVar contains an entry for this variant (Variation ID: 182994). 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 expected to disrupt XRCC2 protein function with a positive predictive value of 80%. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on 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	RCV001016398	SCV001177351	uncertain significance	Hereditary cancer-predisposing syndrome	2024-05-03	criteria provided, single submitter	clinical testing	The p.R91W variant (also known as c.271C>T), located in coding exon 3 of the XRCC2 gene, results from a C to T substitution at nucleotide position 271. The arginine at codon 91 is replaced by tryptophan, an amino acid with dissimilar properties. This alteration has been reported in two Caucasian families with a significant history of breast cancer (Park DJ et al. Am. J. Hum. Genet. 2012 Apr;90:734-9; Hilbers FS et al. PLoS One, 2013 Jan;8:e55734). This alteration was also shown to have a moderate ability to restore XRCC2-DNA repair deficient phenotypes based on its performance in two out of three complementation assays (Hilbers FS et al. Hum. Mutat. 2016 09;37(9):914-25). Additionally, this alteration has been reported in at least one breast cancer patient in a study of 13087 breast cancer cases and 5488 control individuals in the UK (Decker B et al. J Med Genet, 2017 11;54:732-741). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Baylor Genetics	RCV001330061	SCV001521654	uncertain significance	Fanconi anemia complementation group U	2020-06-03	criteria provided, single submitter	clinical testing	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000161106	SCV004221580	uncertain significance	not provided	2023-02-22	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.0000071 (2/282478 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in a family with breast cancer (PMID: 22464251 (2012)). A functional study showed that the variant has a moderate effect on XRCC2 function (PMID: 27233470 (2016)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant.
Leiden Open Variation Database	RCV000161106	SCV001364751	uncertain significance	not provided	2012-05-02	no assertion criteria provided	curation	Curator: Arleen D. Auerbach. Submitter to LOVD: Johan den Dunnen.