7-152649072-C-T

Variant names:

• chr7-152649072-C-T
• rs1060502668
• NM_005431.2:c.413G>A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_005431.2(XRCC2):​c.413G>A​(p.Cys138Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,874 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: XRCC2 NM_005431.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• 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 2 ACMG points.

• 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	c.413G>A	p.Cys138Tyr	missense_variant	Exon 3 of 3	ENST00000359321.2	NP_005422.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
XRCC2	ENST00000359321.2	c.413G>A	p.Cys138Tyr	missense_variant	Exon 3 of 3	1	NM_005431.2	ENSP00000352271.1
XRCC2	ENST00000495707.1	n.435G>A		non_coding_transcript_exon_variant	Exon 3 of 3	1
XRCC2	ENST00000698506.1	c.245G>A	p.Cys82Tyr	missense_variant	Exon 2 of 2			ENSP00000513758.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461874 Hom.: 0 Cov.: 32 AF XY: 0.00000413 AC XY: 3 AN XY: 727236

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000447

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:1

Jul 31, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ClinVar contains an entry for this variant (Variation ID: 409964). 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. 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 expected to disrupt XRCC2 protein function. This variant has not been reported in the literature in individuals affected with XRCC2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 138 of the XRCC2 protein (p.Cys138Tyr). -

Hereditary cancer-predisposing syndrome Uncertain:1

Feb 22, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.C138Y variant (also known as c.413G>A), located in coding exon 3 of the XRCC2 gene, results from a G to A substitution at nucleotide position 413. The cysteine at codon 138 is replaced by tyrosine, an amino acid with highly dissimilar properties. This amino acid position is conserved. In addition, this alteration is predicted to be deleterious by in silico analysis. 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	0.19
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.16
CADD	Uncertain	24
DANN	Uncertain	0.97
DEOGEN2	Benign	0.27	T
Eigen	Uncertain	0.26
Eigen_PC	Benign	0.16
FATHMM_MKL	Benign	0.65	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.026	D
MetaRNN	Uncertain	0.73	D
MetaSVM	Benign	-0.47	T
MutationAssessor	Uncertain	2.7	M
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-2.2	N
REVEL	Uncertain	0.37
Sift	Benign	0.052	T
Sift4G	Uncertain	0.035	D
Polyphen		0.96	D
Vest4		0.75
MutPred		0.43		Loss of catalytic residue at M136 (P = 0.094);
MVP		0.65
MPC		0.33
ClinPred		0.79	D
GERP RS		5.2
Varity_R		0.27
gMVP		0.36

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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;