rs63750582
Variant names:
Your query was ambiguous. Multiple possible variants found:
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_000251.3(MSH2):c.490G>A(p.Gly164Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G164E) has been classified as Pathogenic.
Frequency
Genomes: not found (cov: 31)
Consequence
MSH2
NM_000251.3 missense
NM_000251.3 missense
Scores
12
5
2
Clinical Significance
Conservation
PhyloP100: 9.92
Genes affected
MSH2 (HGNC:7325): (mutS homolog 2) This locus is frequently mutated in hereditary nonpolyposis colon cancer (HNPCC). When cloned, it was discovered to be a human homolog of the E. coli mismatch repair gene mutS, consistent with the characteristic alterations in microsatellite sequences (RER+ phenotype) found in HNPCC. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Apr 2012]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 ACMG points.
PM1
In a strand (size 7) in uniprot entity MSH2_HUMAN there are 9 pathogenic changes around while only 2 benign (82%) in NM_000251.3
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr2-47410218-G-A is described in Lovd as [Pathogenic].
PP3
MetaRNN computational evidence supports a deleterious effect, 0.966
PP5
Variant 2-47410217-G-A is Pathogenic according to our data. Variant chr2-47410217-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 91109.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr2-47410217-G-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
31
GnomAD4 exome Cov.: 32
GnomAD4 exome
Cov.:
32
GnomAD4 genome
GnomAD4 genome
Cov.:
31
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:6Uncertain:1
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
Hereditary nonpolyposis colon cancer Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Feb 09, 2021 | Variant summary: MSH2 c.490G>A (p.Gly164Arg) results in a non-conservative amino acid change located in the DNA mismatch repair protein MutS, connector domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251486 control chromosomes. c.490G>A has been reported in the literature in individuals affected with Hereditary Nonpolyposis Colorectal Cancer (Olila_2006, Mangold_2005, Yurgelun_2015). Experimental evidence shows the variant to result in complete loss of MMR function, with impact on protein stability (Ollila_2006, Olila_2008). No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Lynch syndrome 1 Pathogenic:1
| Likely pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Jul 27, 2023 | This variant is considered likely pathogenic. This variant is expected to disrupt protein structure [Myriad internal data]. Functional studies indicate this variant impacts protein function [PMID: 17101317, 26951660]. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 18951462]. - |
Lynch syndrome Pathogenic:1
| Pathogenic, reviewed by expert panel | research | International Society for Gastrointestinal Hereditary Tumours (InSiGHT) | Sep 05, 2013 | Multifactorial likelihood analysis posterior probability >0.99 - |
not provided Pathogenic:1
| Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Apr 05, 2024 | In silico analysis suggests this variant may impact gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; 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: 18951462, 24362816, 26951660, 17594722, 21120944, 17101317, 33357406, 18822302, 26648449, 15849733, 25980754, 22949387) - |
Hereditary nonpolyposis colorectal neoplasms Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jul 03, 2024 | This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 164 of the MSH2 protein (p.Gly164Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of Lynch syndrome (PMID: 15849733, 17101317; Invitae). ClinVar contains an entry for this variant (Variation ID: 91109). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (Invitae) indicates that this missense variant is expected to disrupt MSH2 function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects MSH2 function (PMID: 17101317, 18951462). This variant disrupts the p.Gly164 amino acid residue in MSH2. Other variant(s) that disrupt this residue have been observed in individuals with MSH2-related conditions (PMID: 26648449; Invitae), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. - |
Hereditary cancer-predisposing syndrome Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 19, 2022 | The p.G164R pathogenic mutation (also known as c.490G>A) is located in coding exon 3 of the MSH2 gene. This alteration results from a G to A substitution at nucleotide position 490. The glycine at codon 164 is replaced by arginine, an amino acid with dissimilar properties. This mutation has been identified in multiple HNPCC/Lynch syndrome kindreds (Mangold et. al, Int J Cancer. 2005; 116(5): 692-702, Ou et al, Hum Mutat. 2007; 28(11): 1047-54, Lucci-Cordisco et. al., Cancer Biomarkers. 2006; 2:11-27). In addition, in an in vitro MMR assay, p.G164R demonstrated complete loss of MMR function (Ollila et al., Gastroent. 2006; 131: 1408). This alteration has been classified as pathogenic by multifactorial analysis, which integrates the following lines of evidence to produce a quantitative likelihood of pathogenicity: in silico prediction models, segregation with disease, tumor characteristics, mutation co-occurrence, and functional assay results (Thompson B et al. Nat Genet. 2014 Feb;46(2):107-15; available at [www.insight-group.org/variants/classifications/]). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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 supporting evidence, this alteration is interpreted as a disease-causing mutation. - |
Lynch-like syndrome Uncertain:1
| Uncertain significance, no assertion criteria provided | clinical testing | Constitutional Genetics Lab, Leon Berard Cancer Center | Jul 01, 2019 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Pathogenic
D;D;.;.;.
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Pathogenic
D;D;D;D;D
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D;D;D;D;D
MetaSVM
Uncertain
D
MutationAssessor
Uncertain
M;.;.;.;.
PrimateAI
Pathogenic
T
PROVEAN
Uncertain
D;D;D;.;D
REVEL
Pathogenic
Sift
Benign
D;D;D;.;D
Sift4G
Uncertain
D;D;D;.;D
Polyphen
D;.;.;.;D
Vest4
MutPred
Gain of MoRF binding (P = 0.0241);.;.;Gain of MoRF binding (P = 0.0241);Gain of MoRF binding (P = 0.0241);
MVP
MPC
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DG_spliceai
Position offset: 1
Find out detailed SpliceAI scores and Pangolin per-transcript scores at