ClinVar Miner

Submissions for variant NM_005431.2(XRCC2):c.659A>T (p.Asp220Val)

gnomAD frequency: 0.00001  dbSNP: rs765021741
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000567327 SCV000675848 uncertain significance Hereditary cancer-predisposing syndrome 2024-05-29 criteria provided, single submitter clinical testing The p.D220V variant (also known as c.659A>T), located in coding exon 3 of the XRCC2 gene, results from an A to T substitution at nucleotide position 659. The aspartic acid at codon 220 is replaced by valine, an amino acid with highly dissimilar properties. This alteration was identified in 1/3548 BRCA1/2-negative familial breast cancer cases and 0/1435 controls (Hilbers FS et al. J. Med. Genet., 2012 Oct;49:618-20). A cDNA complementation assay showed that the DNA repair efficiency of this alteration is similar to wild type (Hilbers FS et al. Hum. Mutat., 2016 09;37:914-25). 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.
Labcorp Genetics (formerly Invitae), Labcorp RCV001066340 SCV001231347 uncertain significance not provided 2024-03-23 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid, which is acidic and polar, with valine, which is neutral and non-polar, at codon 220 of the XRCC2 protein (p.Asp220Val). This variant is present in population databases (rs765021741, gnomAD 0.0009%). This missense change has been observed in individual(s) with breast cancer (PMID: 23054243). ClinVar contains an entry for this variant (Variation ID: 486728). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. Experimental studies have shown that this missense change does not substantially affect 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.
Fulgent Genetics, Fulgent Genetics RCV002483544 SCV002779106 uncertain significance Fanconi anemia complementation group U; Spermatogenic failures 50; Premature ovarian failure 17 2021-09-09 criteria provided, single submitter clinical testing
Leiden Open Variation Database RCV001066340 SCV001364738 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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