rs765021741
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4
The NM_005431.2(XRCC2):c.659A>T(p.Asp220Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000105 in 1,613,882 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 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. D220G) has been classified as Uncertain significance.
Frequency
Consequence
NM_005431.2 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 1 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
XRCC2 | NM_005431.2 | c.659A>T | p.Asp220Val | missense_variant | 3/3 | ENST00000359321.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
XRCC2 | ENST00000359321.2 | c.659A>T | p.Asp220Val | missense_variant | 3/3 | 1 | NM_005431.2 | P1 | |
XRCC2 | ENST00000495707.1 | n.681A>T | non_coding_transcript_exon_variant | 3/3 | 1 | ||||
XRCC2 | ENST00000698506.1 | c.491A>T | p.Asp164Val | missense_variant | 2/2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152198Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251392Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135860
GnomAD4 exome AF: 0.0000103 AC: 15AN: 1461684Hom.: 0 Cov.: 31 AF XY: 0.0000110 AC XY: 8AN XY: 727102
GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152198Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74356
ClinVar
Submissions by phenotype
not provided Uncertain:2
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 | Invitae | Aug 30, 2023 | An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. This sequence change replaces aspartic acid, which is acidic and polar, with valine, which is neutral and non-polar, at codon 220 of the XRCC2 protein (p.Asp220Val). This variant is present in population databases (rs765021741, gnomAD 0.0009%). This missense change has been observed in individual(s) with breast cancer (PMID: 23054243). ClinVar contains an entry for this variant (Variation ID: 486728). Experimental studies have shown that this missense change does not substantially affect XRCC2 function (PMID: 27233470). 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. - |
Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | May 29, 2024 | The p.D220V variant (also known as c.659A>T), located in coding exon 3 of the XRCC2 gene, results from an A to T substitution at nucleotide position 659. The aspartic acid at codon 220 is replaced by valine, an amino acid with highly dissimilar properties. This alteration was identified in 1/3548 BRCA1/2-negative familial breast cancer cases and 0/1435 controls (Hilbers FS et al. J. Med. Genet., 2012 Oct;49:618-20). A cDNA complementation assay showed that the DNA repair efficiency of this alteration is similar to wild type (Hilbers FS et al. Hum. Mutat., 2016 09;37:914-25). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Fanconi anemia complementation group U;C5436888:Spermatogenic failures 50;C5436889:Premature ovarian failure 17 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Sep 09, 2021 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at