ClinVar Miner

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

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 8
Download table as spreadsheet
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 RCV000709051 SCV000838285 uncertain significance Hereditary Cancer 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 2020-01-29 criteria provided, single submitter clinical testing Deficient protein function by in vitro/ex vivo assay;Deficient protein function in appropriate functional assay(s);Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation;Detected in individual(s) satisfying established diagnostic criteria for classic disease in trans with a mutation or mutation is homozygous;Other data supporting pathogenic classification
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.

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.