Submissions for variant NM_005431.2(XRCC2):c.96del (p.Phe32fs)

dbSNP: rs730882048

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000254696	SCV000211850	uncertain significance	not provided	2020-11-10	criteria provided, single submitter	clinical testing	Case-control data do not support that this variant is associated with increased risk for breast cancer (Kluzniak 2019); Frameshift variant predicted to result in protein truncation, as the last 249 amino acids are replaced with 29 different amino acids, disrupting the critical Walker A and Walker B ATPase motifs (O'Regan 2001, Miller 2004); Observed in individuals with breast cancer, at least one of whom also harbored a pathogenic ATM variant (Cybulski 2014, Couch 2015, Shirts 2016); Variants in candidate genes are classified as variants of uncertain significance in accordance with ACMG guidelines (Richards et al., 2015); This variant is associated with the following publications: (PMID: 25330149, 26689913, 25452441, 26681312, 26845104, 30322717, 31463769)
University of Washington Department of Laboratory Medicine, University of Washington	RCV000161115	SCV000266233	uncertain significance	Hereditary cancer-predisposing syndrome	2015-11-20	criteria provided, single submitter	clinical testing
Invitae	RCV000254696	SCV000550368	uncertain significance	not provided	2023-12-25	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Phe32Leufs*30) in the XRCC2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 249 amino acid(s) of the XRCC2 protein. This variant is present in population databases (rs730882048, gnomAD 0.02%). This premature translational stop signal has been observed in individual(s) with breast cancer and ovarian cancer (PMID: 25330149, 25452441, 26681312, 26845104, 30322717, 31463769). This variant is also known as c.95delT. ClinVar contains an entry for this variant (Variation ID: 183003). 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.
CeGaT Center for Human Genetics Tuebingen	RCV000254696	SCV001155336	uncertain significance	not provided	2022-11-01	criteria provided, single submitter	clinical testing	XRCC2: PVS1:Strong
Ambry Genetics	RCV000161115	SCV001181039	likely pathogenic	Hereditary cancer-predisposing syndrome	2023-08-30	criteria provided, single submitter	clinical testing	The c.96delT variant, located in coding exon 2 of the XRCC2 gene, results from a deletion of one nucleotide at nucleotide position 96, causing a translational frameshift with a predicted alternate stop codon (p.F32Lfs*30). The predicted stop codon occurs in the 5’ end of theXRCC2 gene. Premature termination codons in the 5’ end of a gene have been reported to escape nonsense-mediated mRNAdecay and/or lead to re-initiation (Rivas et al. Science. 2015 May 8;348(6235):666-9; Lindeboom et al. Nat Genet. 2016 Oct;48(10):1112-8; Rhee et al. Sci Rep. 2017 May 10;7(1):1653). Direct evidence for this alteration is unavailable, however premature termination codons are typically deleterious in nature. This alteration has been identified in multiple individuals diagnosed with breast and/or ovarian cancer (Couch FJ et al. J. Clin. Oncol. 2015 Feb;33:304-11; Cybulski C et al. Clin. Genet. 2015 Oct;88:366-70; Shirts BH et al. Genet. Med. 2016 Oct;18:974-81; Carter NJ et al. Gynecol Oncol. 2018 12;151:481-488). Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Medical Genetics Laboratory, Umraniye Training and Research Hospital, University of Health Sciences	RCV001640209	SCV001860288	likely pathogenic	Breast carcinoma	2021-09-11	no assertion criteria provided	clinical testing