rs775390721
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 0P and 3B. BP4_ModerateBP6
The ENST00000233146.7(MSH2):āc.2621A>Gā(p.Tyr874Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000013 in 1,461,780 control chromosomes in the GnomAD database, including 1 homozygotes. 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y874H) has been classified as Likely benign.
Frequency
Consequence
ENST00000233146.7 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
MSH2 | NM_000251.3 | c.2621A>G | p.Tyr874Cys | missense_variant | 15/16 | ENST00000233146.7 | NP_000242.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
MSH2 | ENST00000233146.7 | c.2621A>G | p.Tyr874Cys | missense_variant | 15/16 | 1 | NM_000251.3 | ENSP00000233146 | P1 |
Frequencies
GnomAD3 genomes Cov.: 31
GnomAD3 exomes AF: 0.0000199 AC: 5AN: 251406Hom.: 0 AF XY: 0.0000368 AC XY: 5AN XY: 135872
GnomAD4 exome AF: 0.0000130 AC: 19AN: 1461780Hom.: 1 Cov.: 32 AF XY: 0.0000206 AC XY: 15AN XY: 727188
GnomAD4 genome Cov.: 31
ClinVar
Submissions by phenotype
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Mar 23, 2023 | The frequency of this variant in the general population, 0.00016 (5/30610 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in a control individual in a large scale breast cancer association study (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/MSH2)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Jul 09, 2024 | PM2 - |
Hereditary cancer-predisposing syndrome Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 27, 2022 | The p.Y874C variant (also known as c.2621A>G), located in coding exon 15 of the MSH2 gene, results from an A to G substitution at nucleotide position 2621. The tyrosine at codon 874 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration was seen in 1/732 breast cancer patients, 0/189 colorectal cancer patients and 0/490 cancer-free elderly controls in a Turkish population (Akcay IM et al. Int J Cancer, 2021 Jan;148:285-295). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Likely benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Sep 09, 2015 | - - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Sep 24, 2018 | Variant summary: MSH2 c.2621A>G (p.Tyr874Cys) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 246210 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.2621A>G in individuals affected with Lynch Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. - |
MSH2-related disorder Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Dec 03, 2023 | The MSH2 c.2621A>G variant is predicted to result in the amino acid substitution p.Tyr874Cys. This variant has been reported in an individual with breast cancer (Table S6, Akcay et al. 2021. PubMed ID: 32658311). This variant is reported in 0.016% of alleles in individuals of South Asian descent in gnomAD. This variant has conflicting interpretations of benign, likely benign. and uncertain significance in ClinVar (https://preview.ncbi.nlm.nih.gov/clinvar/variation/525750/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
Hereditary nonpolyposis colorectal neoplasms Benign:1
Benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Dec 12, 2023 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at