rs143153871

Positions:

chr7-152648842-G-A

Variant summary

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

The ENST00000359321.2(XRCC2):c.643C>T(p.Arg215Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000446 in 1,613,802 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). Synonymous variant affecting the same amino acid position (i.e. R215R) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000044 ( 0 hom. )

Consequence

XRCC2
ENST00000359321.2 stop_gained

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4U:5

Conservation

PhyloP100: 1.02

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 exon, not predicted to undergo nonsense mediated mRNA decay. There are 4 pathogenic variants in the truncated region.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 7-152648842-G-A is Pathogenic according to our data. Variant chr7-152648842-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 30063.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=3, Uncertain_significance=4}. Variant chr7-152648842-G-A is described in Lovd as [Pathogenic]. Variant chr7-152648842-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
XRCC2	NM_005431.2 linkuse as main transcript	c.643C>T	p.Arg215Ter	stop_gained	3/3	ENST00000359321.2	NP_005422.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
XRCC2	ENST00000359321.2 linkuse as main transcript	c.643C>T	p.Arg215Ter	stop_gained	3/3	1	NM_005431.2	ENSP00000352271	P1
XRCC2	ENST00000495707.1 linkuse as main transcript	n.665C>T		non_coding_transcript_exon_variant	3/3	1
XRCC2	ENST00000698506.1 linkuse as main transcript	c.475C>T	p.Arg159Ter	stop_gained	2/2			ENSP00000513758

Frequencies

GnomAD3 genomes

AF:

0.0000526

AC:

AN:

152134

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

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:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000735

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000398

AC:

AN:

251380

Hom.:

AF XY:

0.0000368

AC XY:

AN XY:

135852

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.000198

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000704

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000438

AC:

AN:

1461550

Hom.:

Cov.:

AF XY:

0.0000344

AC XY:

AN XY:

727010

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.000268

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000477

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000525

AC:

AN:

152252

Hom.:

Cov.:

AF XY:

0.0000806

AC XY:

AN XY:

74442

show subpopulations

Gnomad4 AFR

AF:

0.0000722

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000735

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000800

Hom.:

Bravo

AF:

0.0000340

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000412

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4Uncertain:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Fanconi anemia complementation group U

Pathogenic:1Uncertain:2

Uncertain significance, no assertion criteria provided	literature only	OMIM	Dec 09, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Likely pathogenic, criteria provided, single submitter	research	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Mar 14, 2024	- -

not provided

Pathogenic:1Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 17, 2023	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. Experimental studies have shown that this premature translational stop signal affects XRCC2 function (PMID: 27233470). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. ClinVar contains an entry for this variant (Variation ID: 30063). This premature translational stop signal has been observed in individual(s) with breast cancer, male infertility, and has been observed to be homozygous in an individual with Fanconi anemia (PMID: 22232082, 26046366, 26845104, 28486781, 30306255). This variant is present in population databases (rs143153871, gnomAD 0.02%). This sequence change creates a premature translational stop signal (p.Arg215*) in the XRCC2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 66 amino acid(s) of the XRCC2 protein. -
Pathogenic, no assertion criteria provided	curation	Leiden Open Variation Database	Mar 08, 2017	Curator: Arleen D. Auerbach. Submitter to LOVD: Johan den Dunnen. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jun 27, 2017	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. -

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	Jan 30, 2024	The p.R215* variant (also known as c.643C>T), located in coding exon 3 of the XRCC2 gene, results from a C to T substitution at nucleotide position 643. This changes the amino acid from an arginine to a stop codon within coding exon 3. This alteration occurs at the 3' terminus of theXRCC2 gene and is not expected to trigger nonsense-mediated mRNA decay. However, premature stop codons are typically deleterious in nature and a significant portion of the protein is affected (Ambry internal data). This alteration was detected in a homozygous state in an individual diagnosed with Fanconi anemia who had consanguineous parents (Shamseldin HE et al. J. Med. Genet. 2012 Mar;49:184-6). Functional analyses have shown that p.R215* creates an unstable protein, with increased sensitivity to DNA crosslinking agents similar to other known pathogenic mutations causing Fanconi anemia; reintroduction of wild-type XRCC2 protein in complementation studies restored normal cellular phenotype, providing further evidence for the pathogenicity of p.R215* (Park JY et al. J. Med. Genet. 2016 Oct;53:672-680). Further studies showed that the p.R215* alteration results in less than 50% rescue in two out of three different homologous recombination assays compared to wild-type (Hilbers FS et al. Hum. Mutat. 2016 09;37:914-25). This alteration has also been reported in one breast cancer proband from a cohort of Palestinian breast cancer patients (Lolas Hamameh S et al. Int. J. Cancer. 2017 Aug;141:750-756). In addition, this alteration was reported in a breast cancer proband from a cohort of 192 Spanish families with histories suggestive of hereditary breast and ovarian cancer without a BRCA mutation (Bonache S et al. J. Cancer Res. Clin. Oncol., 2018 Dec;144:2495-2513). While this alteration has been shown to be associated with Fanconi Anemia and lead to impaired protein function, its association with breast cancer remains unclear. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Short stature, microcephaly, and endocrine dysfunction

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Pathology and Clinical Laboratory Medicine, King Fahad Medical City

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.49

BayesDel_noAF

Pathogenic

0.28

CADD

Pathogenic

DANN

Benign

0.97

Eigen

Benign

-0.12

Eigen_PC

Benign

-0.47

FATHMM_MKL

Benign

0.20

MutationTaster

Benign

1.0

Vest4

0.63

GERP RS

1.6

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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