rs730882048
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Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PVS1_StrongPM2
The NM_005431.2(XRCC2):c.96del(p.Phe32LeufsTer30) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000049 in 1,613,350 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.000072 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000047 ( 0 hom. )
Consequence
XRCC2
NM_005431.2 frameshift
NM_005431.2 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 2.54
Genes affected
XRCC2 (HGNC:12829): (X-ray repair cross complementing 2) This gene encodes a member of the RecA/Rad51-related protein family that participates in homologous recombination to maintain chromosome stability and repair DNA damage. This gene is involved in the repair of DNA double-strand breaks by homologous recombination and it functionally complements Chinese hamster irs1, a repair-deficient mutant that exhibits hypersensitivity to a number of different DNA-damaging agents. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
PVS1
?
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. There are 12 pathogenic variants in the truncated region.
PM2
?
Very rare variant in population databases, with high coverage;
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
XRCC2 | NM_005431.2 | c.96del | p.Phe32LeufsTer30 | frameshift_variant | 2/3 | ENST00000359321.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
XRCC2 | ENST00000359321.2 | c.96del | p.Phe32LeufsTer30 | frameshift_variant | 2/3 | 1 | NM_005431.2 | P1 | |
XRCC2 | ENST00000495707.1 | n.118del | non_coding_transcript_exon_variant | 2/3 | 1 | ||||
XRCC2 | ENST00000698506.1 | c.-47-11363del | intron_variant | ||||||
XRCC2 | ENST00000698507.1 | n.164del | non_coding_transcript_exon_variant | 2/2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000723 AC: 11AN: 152192Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000678 AC: 17AN: 250678Hom.: 0 AF XY: 0.0000516 AC XY: 7AN XY: 135540
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GnomAD4 exome AF: 0.0000465 AC: 68AN: 1461158Hom.: 0 Cov.: 30 AF XY: 0.0000564 AC XY: 41AN XY: 726834
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:2Uncertain:4
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Nov 01, 2022 | XRCC2: PVS1:Strong - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Nov 10, 2020 | 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) - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Dec 25, 2023 | 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. - |
Hereditary cancer-predisposing syndrome Pathogenic:1Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | University of Washington Department of Laboratory Medicine, University of Washington | Nov 20, 2015 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 30, 2023 | 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. - |
Breast carcinoma Pathogenic:1
Likely pathogenic, no assertion criteria provided | clinical testing | Medical Genetics Laboratory, Umraniye Training and Research Hospital, University of Health Sciences | Sep 11, 2021 | - - |
Computational scores
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at