rs762701579
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate
The NM_005431.2(XRCC2):āc.7A>Gā(p.Ser3Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000242 in 1,613,716 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. S3S) has been classified as Likely benign.
Frequency
Consequence
NM_005431.2 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 0 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
XRCC2 | NM_005431.2 | c.7A>G | p.Ser3Gly | missense_variant | 1/3 | ENST00000359321.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
XRCC2 | ENST00000359321.2 | c.7A>G | p.Ser3Gly | missense_variant | 1/3 | 1 | NM_005431.2 | P1 | |
XRCC2 | ENST00000698506.1 | c.-80A>G | 5_prime_UTR_variant | 1/2 | |||||
XRCC2 | ENST00000698507.1 | n.75A>G | non_coding_transcript_exon_variant | 1/2 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152222Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000120 AC: 3AN: 250732Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135704
GnomAD4 exome AF: 0.0000260 AC: 38AN: 1461494Hom.: 0 Cov.: 31 AF XY: 0.0000248 AC XY: 18AN XY: 727084
GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152222Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74366
ClinVar
Submissions by phenotype
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | May 07, 2023 | Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The glycine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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. ClinVar contains an entry for this variant (Variation ID: 418820). This missense change has been observed in individual(s) with clinical features of XRCC2-related conditions (PMID: 31159747). This variant is present in population databases (rs762701579, gnomAD 0.003%). This sequence change replaces serine, which is neutral and polar, with glycine, which is neutral and non-polar, at codon 3 of the XRCC2 protein (p.Ser3Gly). - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Apr 29, 2016 | This variant is denoted XRCC2 c.7A>G at the cDNA level, p.Ser3Gly (S3G) at the protein level, and results in the change of a Serine to a Glycine (AGT>GGT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. XRCC2 Ser3Gly was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Serine and Glycine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. XRCC2 Ser3Gly occurs at a position that is conserved in mammals and is not located in a known functional domain (O'Regan 2001, Kim 2011, UniProt). In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available evidence, it is unclear whether XRCC2 Ser3Gly is a pathogenic or benign variant. We consider it to be a variant of uncertain significance. - |
Hereditary cancer-predisposing syndrome Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneKor MSA | Aug 01, 2018 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 08, 2024 | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
XRCC2-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Dec 22, 2022 | The XRCC2 c.7A>G variant is predicted to result in the amino acid substitution p.Ser3Gly. This variant was reported with uncertain significance in study of individuals with a personal or family history of breast and/or ovarian cancer (Supplemental Table S5, Tsaousis et al. 2019. PubMed ID: 31159747). This variant is reported in 0.0031% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/7-152373158-T-C) and is reported as uncertain in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/418820/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at