ClinVar Miner

Submissions for variant NM_005431.2(XRCC2):c.643C>T (p.Arg215Ter) (rs143153871)

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Total submissions: 9
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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.
Mendelics RCV000210083 SCV000838285 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-02 criteria provided, single submitter clinical testing
Invitae RCV000236424 SCV000950846 uncertain significance not provided 2019-01-05 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the last exon of the XRCC2 mRNA at codon 215 (p.Arg215*). While this is not anticipated to result in nonsense mediated decay, it is expected to delete the last 65 amino acids of the XRCC2 protein. This variant is present in population databases (rs143153871, ExAC 0.007%). This variant has been observed in individuals affected with breast cancer (PMID: 26845104, 26046366, 28486781) and has also been observed to be homozygous in an individual affected with Fanconi anemia (PMID: 22232082). ClinVar contains an entry for this variant (Variation ID: 30063). An experimental study has shown that this nonsense change demonstrates partially impaired protein function (PMID: 27233470). The current clinical and genetic evidence is not sufficient to establish whether loss-of-function variants in XRCC2 cause disease. 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.
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 2020-09-10 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 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
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.

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