7-152648641-ATCAACAAAAT-A

Position:

• chr7-152648641-ATCAACAAAAT-A

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1 PM2

The ENST00000359321.2(XRCC2):​c.834_843del​(p.Glu278AspfsTer16) variant causes a frameshift, stop lost change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. E278E) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: XRCC2 ENST00000359321.2 frameshift, stop_lost
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 7.34

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 Pathogenic. Variant got 10 ACMG points.

• PVS1: Stoplost variant. No alternative stopcodon identified downstream, so we assume a Nonstop Mediated Decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
XRCC2	NM_005431.2	c.834_843del	p.Glu278AspfsTer16	frameshift_variant, stop_lost	3/3	ENST00000359321.2	NP_005422.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
XRCC2	ENST00000359321.2	c.834_843del	p.Glu278AspfsTer16	frameshift_variant, stop_lost	3/3	1	NM_005431.2	ENSP00000352271	P1
XRCC2	ENST00000495707.1	n.856_865del		non_coding_transcript_exon_variant	3/3	1
XRCC2	ENST00000698506.1	c.666_675del	p.Glu222AspfsTer16	frameshift_variant, stop_lost	2/2			ENSP00000513758

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

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

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 13, 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 and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. ClinVar contains an entry for this variant (Variation ID: 1762998). 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 results in a frameshift in the XRCC2 gene (p.Glu278Aspfs*16). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 3 amino acid(s) of the XRCC2 protein and extend the protein by 12 additional amino acid residues. -

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 12, 2023

The c.834_843del10 variant, located in coding exon 3 of the XRCC2 gene, results from a deletion of 10 nucleotides at nucleotide positions 834 to 843, causing a translational frameshift with a predicted alternate stop codon (p.E278Dfs*16). This alteration occurs at the 3' terminus of theXRCC2 gene, is not expected to trigger nonsense-mediated mRNAdecay and results in the elongation of the protein by 12 amino acids. This frameshift impacts the last 3amino acids of the native protein. The exact functional effect of the altered amino acids is unknown. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Splicing

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: chr7-152345726;