Submissions for variant NM_005431.2(XRCC2):c.651_652del (p.Cys217_Asp218delinsTer)

dbSNP: rs746142129

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000481321	SCV000568373	uncertain significance	not provided	2017-07-13	criteria provided, single submitter	clinical testing	This deletion of 2 nucleotides is denoted XRCC2 c.651_652delTG at the cDNA level and p.Cys217Ter (C217X) at the protein level. The normal sequence, with the bases that are deleted in brackets, is TGTG[delTG]ATGT. The deletion creates a nonsense variant, which changes a Cysteine to a premature stop codon. Due to the position of the variant, XRCC2 Cys217Ter is not expected to undergo nonsense-mediated decay, but results in the loss of 64 amino acids at the end of the protein which might cause loss of normal protein function through protein truncation. The disrupted region at the end of the gene is not within any known functional domain (OÂ’Regan 2001, Miller 2004). XRCC2 Cys217Ter has been reported in at least two individuals with a personal history of breast cancer; however, one of these individuals was also found to harbor a truncating variant in BRCA1 (Park 2012). This variant was shown to retain some homologous recombination activity in an in vitro functional assay (Hilbers 2016). Based on currently available information, it is unclear whether this deletion is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics	RCV001025359	SCV001187532	likely pathogenic	Hereditary cancer-predisposing syndrome	2022-11-15	criteria provided, single submitter	clinical testing	The c.651_652delTG variant, located in coding exon 3 of the XRCC2 gene, results from a deletion of two nucleotides at nucleotide positions 651 to 652, causing a translational frameshift with a predicted alternate stop codon (p.C217*). This frameshift occurs at the 3' terminus of XRCC2, is not expected to trigger nonsense-mediated mRNA decay, and impacts only the last 64 amino acids of the protein. Functional studies using c-DNA complementation assays demonstrate that this alteration results in a partial loss (31% of wildtype) of ability to restore XRCC2 deficiency (Hilbers FS et al. Hum. Mutat., 2016 Sep;37:914-25). In addition, p.C217* has been reported in multiple hereditary breast and/or ovarian cancer cohorts, including individuals with early-onset breast cancer and male breast cancer (Park DJ et al. Am. J. Hum. Genet., 2012 Apr;90:734-9; Young E et al. J. Med. Genet. 2016 06;53(6):366-76; Golmard L et al. Eur. J. Hum. Genet. 2017 12;25(12):1345-1353; Thompson E et al. J. Clin. Oncol. 2016 May;34(13):1455-9). Based on the majority of evidence to date, this alteration is interpreted as likely pathogenic.
Invitae	RCV000481321	SCV001406290	uncertain significance	not provided	2023-11-24	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Cys217*) in the XRCC2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 64 amino acid(s) of the XRCC2 protein. 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 premature translational stop signal has been observed in individual(s) with a personal and/or family history of breast cancer or ovarian cancer (PMID: 22464251, 26786923, 29255180). ClinVar contains an entry for this variant (Variation ID: 420029). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this premature translational stop signal affects 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.
Revvity Omics, Revvity	RCV000481321	SCV003823837	uncertain significance	not provided	2019-08-15	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000481321	SCV004221594	likely pathogenic	not provided	2023-06-20	criteria provided, single submitter	clinical testing	The XRCC2 c.651_652del (p.Cys217*) variant is predicted to cause the premature termination of XRCC2 protein synthesis, however due to the position of the variant, it is not expected to result in nonsense mediated decay. This variant has been reported in the published literature in individuals with a personal or family history of breast and/or ovarian cancer (PMIDs: 29255180 (2017), 26786923 (2016), 22464251 (2012)) and Fanconi Anemia (PMID: 31980526 (2020)), as well as healthy individuals (PMID: 22464251 (2012)). The frequency of this variant in the general population, 0.000039 (5/129152 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Based on the available information, this variant is classified as likely pathogenic.
Leiden Open Variation Database	RCV000481321	SCV001364737	uncertain significance	not provided	2012-05-02	no assertion criteria provided	curation	Curator: Arleen D. Auerbach. Submitter to LOVD: Johan den Dunnen.