rs1060502668

chr7-152649072-C-Gchr7-152649072-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_005431.2(XRCC2):c.413G>C(p.Cys138Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C138Y) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: XRCC2 NM_005431.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.79

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.40449804).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
XRCC2	NM_005431.2	c.413G>C	p.Cys138Ser	missense_variant	3/3	ENST00000359321.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
XRCC2	ENST00000359321.2	c.413G>C	p.Cys138Ser	missense_variant	3/3	1	NM_005431.2	P1
XRCC2	ENST00000495707.1	n.435G>C		non_coding_transcript_exon_variant	3/3	1
XRCC2	ENST00000698506.1	c.245G>C	p.Cys82Ser	missense_variant	2/2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 16, 2023

The p.C138S variant (also known as c.413G>C), located in coding exon 3 of the XRCC2 gene, results from a G to C substitution at nucleotide position 413. The cysteine at codon 138 is replaced by serine, an amino acid with dissimilar properties. 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	Benign	0.14
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.070
Cadd	Benign	17
Dann	Benign	0.31
DEOGEN2	Benign	0.097	T
Eigen	Benign	-0.62
Eigen_PC	Benign	-0.48
FATHMM_MKL	Benign	0.69	D
LIST_S2	Benign	0.79	T
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.40	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.1	L
MutationTaster	Benign	0.96	N
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-0.43	N
REVEL	Uncertain	0.29
Sift	Benign	1.0	T
Sift4G	Benign	0.30	T
Polyphen		0.024	B
Vest4		0.68
MutPred		0.38		Gain of disorder (P = 1e-04);
MVP		0.41
MPC		0.29
ClinPred		0.39	T
GERP RS		5.2
Varity_R		0.20
gMVP		0.17

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

Other links and lift over

dbSNP: rs1060502668; hg19: chr7-152346157;