rs587780130
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4
The NM_005431.2(XRCC2):c.667T>C(p.Tyr223His) variant causes a missense change. The variant allele was found at a frequency of 0.0000489 in 1,614,008 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. Y223C) 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.667T>C | p.Tyr223His | missense_variant | 3/3 | ENST00000359321.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
XRCC2 | ENST00000359321.2 | c.667T>C | p.Tyr223His | missense_variant | 3/3 | 1 | NM_005431.2 | P1 | |
XRCC2 | ENST00000495707.1 | n.689T>C | non_coding_transcript_exon_variant | 3/3 | 1 | ||||
XRCC2 | ENST00000698506.1 | c.499T>C | p.Tyr167His | missense_variant | 2/2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000197 AC: 3AN: 152218Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000318 AC: 8AN: 251420Hom.: 0 AF XY: 0.0000442 AC XY: 6AN XY: 135874
GnomAD4 exome AF: 0.0000520 AC: 76AN: 1461790Hom.: 0 Cov.: 31 AF XY: 0.0000481 AC XY: 35AN XY: 727176
GnomAD4 genome ? AF: 0.0000197 AC: 3AN: 152218Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74364
ClinVar
Submissions by phenotype
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Nov 29, 2023 | This sequence change replaces tyrosine, which is neutral and polar, with histidine, which is basic and polar, at codon 223 of the XRCC2 protein (p.Tyr223His). This variant is present in population databases (rs587780130, gnomAD 0.006%). This variant has not been reported in the literature in individuals affected with XRCC2-related conditions. ClinVar contains an entry for this variant (Variation ID: 127962). 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 not expected to disrupt XRCC2 protein function with a negative predictive value of 80%. 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Aug 02, 2022 | In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; Variants in candidate genes are classified as variants of uncertain significance in accordance with ACMG guidelines (Richards et al., 2015) - |
Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Apr 26, 2022 | The p.Y223H variant (also known as c.667T>C), located in coding exon 3 of the XRCC2 gene, results from a T to C substitution at nucleotide position 667. The tyrosine at codon 223 is replaced by histidine, an amino acid with similar properties. This alteration has been reported in at least one breast cancer patient in a study of 13087 breast cancer cases and 5488 control individuals in the UK (Decker B et al. J Med Genet, 2017 11;54:732-741). This amino acid position is 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at