Variant rs730882048 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PVS1_StrongPM2

The NM_005431.2(XRCC2):c.96delT(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

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:5

Conservation

PhyloP100: 2.54

Variant links:

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]

XRCC2 links:

Genome browser will be placed here

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. Fraction of 0.886 CDS is truncated, and there are 2 pathogenic variants in the truncated region.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
XRCC2	NM_005431.2 link	c.96delT	p.Phe32LeufsTer30	frameshift_variant	Exon 2 of 3	ENST00000359321.2	NP_005422.1	O43543A0A384MEK2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
XRCC2	ENST00000359321.2 link	c.96delT	p.Phe32LeufsTer30	frameshift_variant	Exon 2 of 3	1	NM_005431.2	ENSP00000352271.1	O43543
XRCC2	ENST00000495707.1 link	n.118delT		non_coding_transcript_exon_variant	Exon 2 of 3	1
XRCC2	ENST00000698506.1 link	c.-47-11363delT		intron_variant	Intron 1 of 1			ENSP00000513758.1	A0A8V8TMB7
XRCC2	ENST00000698507.1 link	n.164delT		non_coding_transcript_exon_variant	Exon 2 of 2

Frequencies

GnomAD3 genomes

AF:

0.0000723

AC:

AN:

152192

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000943

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000678

AC:

AN:

250678

Hom.:

AF XY:

0.0000516

AC XY:

AN XY:

135540

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000150

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000465

AC:

AN:

1461158

Hom.:

Cov.:

AF XY:

0.0000564

AC XY:

AN XY:

726834

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000594

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000723

AC:

AN:

152192

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74346

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000943

Gnomad4 NFE

AF:

0.000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000145

Hom.:

Bravo

AF:

0.0000869

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2Uncertain:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:4

Nov 10, 2020

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: 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) -

Aug 27, 2024

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The XRCC2 c.96del (p.Phe32Leufs*30) variant alters the translational reading frame of the XRCC2 mRNA and is predicted to cause the premature termination of XRCC2 protein synthesis. This variant is not expected to trigger nonsense mediated decay (NMD), however ~89% of the protein is disrupted, and thus predicted to significantly impact protein function. In the published literature, this variant has been reported in individuals with breast cancer (PMID: 39003306 (2024), 36290365 (2022), 31463769 (2019), 31173646 (2019), 25452441 (2015), 26681312 (2015), 25330149 (2015)), ovarian cancer (PMID: 36290365 (2022), 30322717 (2018), 29053726 (2017)), melanoma (PMID: 29641532 (2018)), and gastric cancer (PMID: 36290365 (2022)). This variant has also been identified in reportedly healthy individuals (PMID: 31463769 (2019), 29641532 (2018)). The frequency of this variant in the general population, 0.00015 (19/128916 chromosomes in European (Non-Finnish) subpopulation (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is higher than would generally be expected for pathogenic variants in this gene. Based on the available information, we are unable to determine the clinical significance of this variant. -

Jan 08, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: 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, 35988656). 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. -

Jan 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

XRCC2: PVS1:Strong -

Hereditary cancer-predisposing syndrome

Pathogenic:1Uncertain:1

Nov 20, 2015

University of Washington Department of Laboratory Medicine, University of Washington

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 15, 2024

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: 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. -

Breast carcinoma

Pathogenic:1

Sep 11, 2021

Medical Genetics Laboratory, Umraniye Training and Research Hospital, University of Health Sciences

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over