7-152648658-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_005431.2(XRCC2):c.827G>A(p.Gly276Glu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic 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. G276R) 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: 4.59

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.847

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
XRCC2	NM_005431.2	c.827G>A	p.Gly276Glu	missense_variant	3/3	ENST00000359321.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
XRCC2	ENST00000359321.2	c.827G>A	p.Gly276Glu	missense_variant	3/3	1	NM_005431.2	P1
XRCC2	ENST00000495707.1	n.849G>A		non_coding_transcript_exon_variant	3/3	1
XRCC2	ENST00000698506.1	c.659G>A	p.Gly220Glu	missense_variant	2/2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

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

Jul 30, 2023

The p.G276E variant (also known as c.827G>A), located in coding exon 3 of the XRCC2 gene, results from a G to A substitution at nucleotide position 827. The glycine at codon 276 is replaced by glutamic acid, an amino acid with similar 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	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.39
Cadd	Pathogenic	26
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.46	T
Eigen	Pathogenic	0.70
Eigen_PC	Pathogenic	0.66
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.79	T
M_CAP	Uncertain	0.17	D
MetaRNN	Pathogenic	0.85	D
MetaSVM	Pathogenic	0.91	D
MutationAssessor	Uncertain	2.7	M
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.55	T
PROVEAN	Pathogenic	-4.8	D
REVEL	Pathogenic	0.81
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.82
MutPred		0.57		Gain of disorder (P = 0.0434);
MVP		0.97
MPC		0.30
ClinPred		1.0	D
GERP RS		5.4
Varity_R		0.87
gMVP		0.80

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr7-152345743;