7-152648771-C-G

Position:

chr7-152648771-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_005431.2(XRCC2):c.714G>C(p.Arg238Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000186 in 1,614,158 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 Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

XRCC2
NM_005431.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:5

Conservation

PhyloP100: -0.958

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:

XRCC2 (HGNC:):

XRCC2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.868

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
XRCC2	NM_005431.2 linkuse as main transcript	c.714G>C	p.Arg238Ser	missense_variant	3/3	ENST00000359321.2	NP_005422.1	O43543A0A384MEK2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
XRCC2	ENST00000359321.2 linkuse as main transcript	c.714G>C	p.Arg238Ser	missense_variant	3/3	1	NM_005431.2	ENSP00000352271.1	O43543
XRCC2	ENST00000495707.1 linkuse as main transcript	n.736G>C		non_coding_transcript_exon_variant	3/3	1
XRCC2	ENST00000698506.1 linkuse as main transcript	c.546G>C	p.Arg182Ser	missense_variant	2/2			ENSP00000513758.1	A0A8V8TMB7

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152160

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

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:

0.00

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251470

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135906

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461880

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727236

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:

0.00

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152278

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74454

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000473

Bravo

AF:

0.0000491

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Dec 11, 2017	This variant is denoted XRCC2 c.714G>C at the cDNA level, p.Arg238Ser (R238S) at the protein level, and results in the change of an Arginine to a Serine (AGG>AGC). This variant has been reported in at least one individual with breast cancer, and in XRCC2-deficient hamster cells was able to restore RAD51C foci formation to 77% of wild-type (Hilbers 2012, Hilbers 2016). XRCC2 Arg238Ser was not observed at a significant allele frequency in large population cohorts (Lek 2016). Since Arginine and Serine differ in some properties, this is considered a semi-conservative amino acid substitution. XRCC2 Arg238Ser is not located in a known functional domain. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Based on currently available evidence, it is unclear whether XRCC2 Arg238Ser is a pathogenic or benign variant. We consider it to be a variant of uncertain significance. -
Uncertain significance, no assertion criteria provided	curation	Leiden Open Variation Database	Apr 14, 2016	Curator: Arleen D. Auerbach. Submitter to LOVD: Florentine Hilbers. -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 04, 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 missense change does not substantially affect XRCC2 function (PMID: 27233470). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt XRCC2 protein function. ClinVar contains an entry for this variant (Variation ID: 240163). This missense change has been observed in individual(s) with breast cancer (PMID: 23054243). This variant is present in population databases (rs534746330, gnomAD 0.003%). This sequence change replaces arginine, which is basic and polar, with serine, which is neutral and polar, at codon 238 of the XRCC2 protein (p.Arg238Ser). -

Fanconi anemia complementation group U

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Mendelics

May 28, 2019

- -

Hereditary cancer-predisposing syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 31, 2023

The p.R238S variant (also known as c.714G>C), located in coding exon 3 of the XRCC2 gene, results from a G to C substitution at nucleotide position 714. The arginine at codon 238 is replaced by serine, an amino acid with dissimilar properties. In one study, this alteration was reported in 1/3548 non-BRCA1/2 familial breast cancer cases and 0/1435 healthy controls (Hilbers FS et al. J Med Genet, 2012 Oct;49:618-20). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.82

BayesDel_addAF

Uncertain

0.045

BayesDel_noAF

Benign

-0.090

CADD

Benign

DANN

Uncertain

0.97

DEOGEN2

Benign

0.39

Eigen

Benign

-0.66

Eigen_PC

Benign

-0.97

FATHMM_MKL

Benign

0.21

LIST_S2

Benign

0.78

M_CAP

Benign

0.036

MetaRNN

Pathogenic

0.87

MetaSVM

Uncertain

-0.090

MutationAssessor

Uncertain

2.7

PrimateAI

Benign

0.46

PROVEAN

Uncertain

-4.1

REVEL

Uncertain

0.44

Sift

Benign

0.11

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.93

MutPred

0.69

Loss of MoRF binding (P = 0.0469);

MVP

0.52

MPC

0.28

ClinPred

0.93

GERP RS

-7.7

Varity_R

0.42

gMVP

0.87

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