rs587779150
Variant summary
Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2BP4_ModerateBP6
The NM_000251.3(MSH2):āc.2567A>Gā(p.Tyr856Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,818 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y856F) has been classified as Uncertain significance.
Frequency
Consequence
NM_000251.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -1 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MSH2 | NM_000251.3 | c.2567A>G | p.Tyr856Cys | missense_variant | 15/16 | ENST00000233146.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MSH2 | ENST00000233146.7 | c.2567A>G | p.Tyr856Cys | missense_variant | 15/16 | 1 | NM_000251.3 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 31
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251450Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135892
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461818Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 727210
GnomAD4 genome ? Cov.: 31
ClinVar
Submissions by phenotype
Lynch syndrome 1 Uncertain:4
Uncertain significance, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Mar 22, 2023 | This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Dec 31, 2023 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Feb 08, 2017 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Division of Medical Genetics, University of Washington | Nov 25, 2019 | To our knowledge, this sequence variant has not been previously reported in the literature. This variant has an overall allele frequency of 0.000004 in the Broad Institute gnomAD Browser (https://gnomad.broadinstitute.org/). In silico analyses indicate that this variant does not alter protein structure/function. Thus, it is unknown at this time whether this variant increases cancer risk. PM2; BP4 - |
Hereditary cancer-predisposing syndrome Uncertain:1Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 12, 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Aug 06, 2018 | - - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Jul 30, 2020 | DNA sequence analysis of the MSH2 gene demonstrated a sequence change, c.2567A>G, in exon 15 that results in an amino acid change, p.Tyr856Cys. This sequence change does not appear to have been previously described in patients with MSH2-related disorders and has been described in the gnomAD database in one individual, with a low overall population frequency of 0.0003% (dbSNP rs587779150). The p.Tyr856Cys change affects a poorly conserved amino acid residue located in a domain of the MSH2 protein that is known to be functional. The p.Tyr856Cys substitution appears to be benign using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Due to these contrasting evidences and the lack of functional studies, the clinical significance of the p.Tyr856Cys change remains unknown at this time. - |
Hereditary nonpolyposis colorectal neoplasms Benign:1
Benign, criteria provided, single submitter | clinical testing | Invitae | Oct 07, 2022 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at