rs750903875

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PVS1_StrongPM2PP5

The NM_005431.2(XRCC2):c.49C>T(p.Arg17Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.000011 in 1,459,546 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.000011 ( 0 hom. )

Consequence

XRCC2
NM_005431.2 stop_gained

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:2

Conservation

PhyloP100: 3.81

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 7 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 13 pathogenic variants in the truncated region.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 7-152660773-G-A is Pathogenic according to our data. Variant chr7-152660773-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 486731.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Likely_pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
XRCC2	NM_005431.2 linkuse as main transcript	c.49C>T	p.Arg17Ter	stop_gained	2/3	ENST00000359321.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
XRCC2	ENST00000359321.2 linkuse as main transcript	c.49C>T	p.Arg17Ter	stop_gained	2/3	1	NM_005431.2	P1
XRCC2	ENST00000495707.1 linkuse as main transcript	n.71C>T		non_coding_transcript_exon_variant	2/3	1
XRCC2	ENST00000698506.1 linkuse as main transcript	c.-47-11410C>T		intron_variant
XRCC2	ENST00000698507.1 linkuse as main transcript	n.117C>T		non_coding_transcript_exon_variant	2/2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000120

AC:

AN:

249298

Hom.:

AF XY:

0.00000741

AC XY:

AN XY:

134918

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000292

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000330

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000885

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000110

AC:

AN:

1459546

Hom.:

Cov.:

AF XY:

0.0000110

AC XY:

AN XY:

726054

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000450

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000117

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000990

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000279

Hom.:

Bravo

AF:

0.00000378

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Uncertain significance, no assertion criteria provided	curation	Leiden Open Variation Database	May 02, 2012	Curator: Arleen D. Auerbach. Submitter to LOVD: Johan den Dunnen. -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Dec 11, 2019	This variant has been observed in individuals with breast cancer (PMID: 22464251, 28724667). ClinVar contains an entry for this variant (Variation ID: 486731). 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. The current clinical and genetic evidence is not sufficient to establish whether loss-of-function variants in XRCC2 cause disease. This variant has been reported to have conflicting or insufficient data to determine the effect on XRCC2 protein function (PMID: 27233470). This variant is present in population databases (rs750903875, ExAC 0.006%). This sequence change creates a premature translational stop signal (p.Arg17*) in the XRCC2 gene. It is expected to result in an absent or disrupted protein product. -

Hereditary cancer-predisposing syndrome

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 31, 2022

The p.R17* variant (also known as c.49C>T), located in coding exon 2 of the XRCC2 gene, results from a C to T substitution at nucleotide position 49. This changes the amino acid from an arginine to a stop codon within coding exon 2. 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 individuals with familial breast cancer (Park DJ et al. Am. J. Hum. Genet., 2012 Apr;90:734-9; Sun J et al. Clin. Cancer Res. 2017 Oct;23(20):6113-6119). In a functional study, this alteration was used as a negative control, however, it had unexpectedly high rescue activity in both Rad51C foci formation and homologous repair activity compared to other, longer, truncating mutations. This study ruled out the possibility of a translational start site after amino acid 17 but did identify some read-through of translation at this new TGA stop codon that could explain the higher level of function in these in vitro assays (Hilbers FS et al. Hum. Mutat., 2016 Sep;37:914-25). Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.55

BayesDel_noAF

Pathogenic

0.62

Cadd

Pathogenic

Dann

Uncertain

1.0

Eigen

Pathogenic

0.79

Eigen_PC

Uncertain

0.66

FATHMM_MKL

Uncertain

0.87

MutationTaster

Benign

1.0

Vest4

0.88

GERP RS

5.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.21

Details are displayed if max score is > 0.2

DS_AL_spliceai

0.21

Position offset: 9

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