Submissions for variant NM_005431.2(XRCC2):c.643C>T (p.Arg215Ter)

gnomAD frequency: 0.00006  dbSNP: rs143153871

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
University of Washington Department of Laboratory Medicine, University of Washington	RCV000210083	SCV000266232	uncertain significance	Hereditary cancer-predisposing syndrome	2015-11-20	criteria provided, single submitter	clinical testing
GeneDx	RCV000236424	SCV000292822	uncertain significance	not provided	2017-06-27	criteria provided, single submitter	clinical testing	This variant is denoted XRCC2 c.643C>T at the cDNA level and p.Arg215Ter (R215X) at the protein level. The substitution creates a nonsense variant, which changes an Arginine to a premature stop codon (CGA>TGA) in the last exon of the gene. XRCC2 Arg215Ter was detected in the apparent homozygous state in a child undergoing whole exome sequencing, the offspring of consanguineous parents, who had features suggestive of Fanconi Anemia (Shamseldin 2012). This variant has also been observed in at least two individuals with a personal history or breast cancer (Shirts 2016, Lolas Hamameh 2017). However, this variant was also identified in 1/951 individuals with atherosclerosis, with no significant personal or family history of cancer (Johnston 2015). This variant results in the loss of the last 66 amino acids of the protein for which the clinical significance is unknown. This variant was observed at an allele frequency of 0.007% (5/66,720) in individuals of European non-Finnish ancestry in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016).The lost region is not within any known functional domain (O'Regan 2001). Based on the currently available information, we consider XRCC2 Arg215Ter to be a variant of uncertain significance.
Invitae	RCV000236424	SCV000950846	uncertain significance	not provided	2023-08-17	criteria provided, single submitter	clinical testing	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. Experimental studies have shown that this premature translational stop signal affects XRCC2 function (PMID: 27233470). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. ClinVar contains an entry for this variant (Variation ID: 30063). This premature translational stop signal has been observed in individual(s) with breast cancer, male infertility, and has been observed to be homozygous in an individual with Fanconi anemia (PMID: 22232082, 26046366, 26845104, 28486781, 30306255). This variant is present in population databases (rs143153871, gnomAD 0.02%). This sequence change creates a premature translational stop signal (p.Arg215*) in the XRCC2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 66 amino acid(s) of the XRCC2 protein.
Mendelics	RCV000022966	SCV001137560	uncertain significance	Fanconi anemia complementation group U	2019-05-28	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000210083	SCV001187421	likely pathogenic	Hereditary cancer-predisposing syndrome	2024-01-30	criteria provided, single submitter	clinical testing	The p.R215* variant (also known as c.643C>T), located in coding exon 3 of the XRCC2 gene, results from a C to T substitution at nucleotide position 643. This changes the amino acid from an arginine to a stop codon within coding exon 3. This alteration occurs at the 3' terminus of theXRCC2 gene and is not expected to trigger nonsense-mediated mRNA decay. However, premature stop codons are typically deleterious in nature and a significant portion of the protein is affected (Ambry internal data). This alteration was detected in a homozygous state in an individual diagnosed with Fanconi anemia who had consanguineous parents (Shamseldin HE et al. J. Med. Genet. 2012 Mar;49:184-6). Functional analyses have shown that p.R215* creates an unstable protein, with increased sensitivity to DNA crosslinking agents similar to other known pathogenic mutations causing Fanconi anemia; reintroduction of wild-type XRCC2 protein in complementation studies restored normal cellular phenotype, providing further evidence for the pathogenicity of p.R215* (Park JY et al. J. Med. Genet. 2016 Oct;53:672-680). Further studies showed that the p.R215* alteration results in less than 50% rescue in two out of three different homologous recombination assays compared to wild-type (Hilbers FS et al. Hum. Mutat. 2016 09;37:914-25). This alteration has also been reported in one breast cancer proband from a cohort of Palestinian breast cancer patients (Lolas Hamameh S et al. Int. J. Cancer. 2017 Aug;141:750-756). In addition, this alteration was reported in a breast cancer proband from a cohort of 192 Spanish families with histories suggestive of hereditary breast and ovarian cancer without a BRCA mutation (Bonache S et al. J. Cancer Res. Clin. Oncol., 2018 Dec;144:2495-2513). While this alteration has been shown to be associated with Fanconi Anemia and lead to impaired protein function, its association with breast cancer remains unclear. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Pathology and Clinical Laboratory Medicine, King Fahad Medical City	RCV001261591	SCV001438863	likely pathogenic	Short stature, microcephaly, and endocrine dysfunction		criteria provided, single submitter	clinical testing
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	RCV000022966	SCV004801236	likely pathogenic	Fanconi anemia complementation group U	2024-03-14	criteria provided, single submitter	research
OMIM	RCV000022966	SCV000044257	uncertain significance	Fanconi anemia complementation group U	2016-12-09	no assertion criteria provided	literature only
Leiden Open Variation Database	RCV000236424	SCV001364736	pathogenic	not provided	2017-03-08	no assertion criteria provided	curation	Curator: Arleen D. Auerbach. Submitter to LOVD: Johan den Dunnen.