chr2-47800889-A-G
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM5PP3_StrongPP5_Very_Strong
The NM_000179.3(MSH6):c.2906A>G(p.Tyr969Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000623 in 1,604,754 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y969F) has been classified as Uncertain significance.
Frequency
Consequence
NM_000179.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MSH6 | NM_000179.3 | c.2906A>G | p.Tyr969Cys | missense_variant | 4/10 | ENST00000234420.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MSH6 | ENST00000234420.11 | c.2906A>G | p.Tyr969Cys | missense_variant | 4/10 | 1 | NM_000179.3 | P4 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152222Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000124 AC: 3AN: 242800Hom.: 0 AF XY: 0.0000153 AC XY: 2AN XY: 131144
GnomAD4 exome AF: 0.00000620 AC: 9AN: 1452532Hom.: 0 Cov.: 34 AF XY: 0.00000693 AC XY: 5AN XY: 721698
GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152222Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1AN XY: 74376
ClinVar
Submissions by phenotype
Lynch syndrome 5 Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Aug 21, 2023 | This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [Myriad internal data]. This variant is expected to disrupt protein structure [Myriad internal data]. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 16813607,19723918, 20587412]. - |
Likely pathogenic, criteria provided, single submitter | research | Centre for Mendelian Genomics, University Medical Centre Ljubljana | Dec 09, 2022 | PS4_STR, PM5, PP1 - |
not provided Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Aug 07, 2023 | Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 16813607, 23621914, 19723918, 20587412, 29922827, 36988593, 30536544, 34178123, 34667028, Basel-Salmon2023[CaseReport], 34172528) - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Jul 08, 2022 | - - |
Lynch syndrome 1 Pathogenic:1
Likely pathogenic, reviewed by expert panel | curation | International Society for Gastrointestinal Hereditary Tumours (InSiGHT) | Mar 09, 2018 | Class 4 - Likely Pathogenic Classification using multifactorial probability: 0.9528 - |
Gastric cancer Pathogenic:1
Pathogenic, no assertion criteria provided | research | Laboratory for Genotyping Development, RIKEN | Jul 01, 2021 | - - |
Hereditary nonpolyposis colorectal neoplasms Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Feb 14, 2023 | This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 969 of the MSH6 protein (p.Tyr969Cys). This variant is present in population databases (rs63749919, gnomAD 0.003%). This missense change has been observed in individuals with Lynch syndrome (PMID: 16813607, 19723918, 20587412). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 234622). 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 expected to disrupt MSH6 protein function. For these reasons, this variant has been classified as Pathogenic. - |
Hereditary cancer-predisposing syndrome Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 28, 2022 | The p.Y969C variant (also known as c.2906A>G), located in coding exon 4 of the MSH6 gene, results from an A to G substitution at nucleotide position 2906. The tyrosine at codon 969 is replaced by cysteine, an amino acid with highly dissimilar properties. This variant has been identified in a proband(s) who met Amsterdam I/II criteria for Lynch syndrome and tumor demonstrated high microsatellite instability and/or loss of MSH6 expression by immunohistochemistry (Grindedal EM et al. Cancer Epidemiol. Biomarkers Prev. 2009 Sep;18(9):2460-7; Sjursen W et al. J. Med. Genet. 2010 Sep;47(9):579-85). This variant has also been identified in a proband(s) whose Lynch syndrome-associated tumor demonstrated high microsatellite instability and/or loss of MSH6 expression by immunohistochemistry (Suchy J et al. Clin Genet. 2006 Jul;70(1):68-70; Ambry internal data). This variant has also been reported in an individual from a cohort of adult optic glioma patients (Sa JK et al. Int. J. Cancer. 2019 06;144:3023-3030). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. - |
Endometrial carcinoma Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Aug 13, 2022 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at