Genetic Information
Gene & Transcript Details
| ID | Status | Details |
|---|---|---|
| NM_000251.3 | MANE Select | 3115 nt | 37–2841 |
| NM_000251.1 | Alternative | 3145 nt | 69–2873 |
| NM_000251.2 | RefSeq Select | 3226 nt | 126–2930 |
Variant Details
Clinical & Population Data
Population Frequency
gnomADClinVar
OpenVariant summary: MSH2 c.67T>C (p.Phe23Leu) results in a non-conservative amino acid change located in the DNA mismatch repair protein MutS-like, N-terminal domain of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00057 in 246202 control chromosomes, predominantly within the South Asian subpopulation in the gnomAD database at a frequency of 0.0049, including 2 homozygotes. This frequency within South Asian control individuals is approximately 9-fold above the estimated maximal expected allele frequency for a pathogenic variant in MSH2 causing Lynch Syndrome phenotype (0.00057), strongly suggesting that the variant is a benign polymorphism found primarily in populations of South Asian origin. The variant has been reported in a patient with gastrointestinal stromal cancer, but without evidence of causality. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign.
This variant is considered benign. This variant has been observed in trans with a known pathogenic variant in one or more individuals lacking clinical features consistent with gene-specific recessive disease. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 27363726].
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
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.
"This variant has been reported in ClinVar as Benign (7 clinical laboratories) and as Likely benign (5 clinical laboratories) and as Uncertain significance (1 clinical laboratories)."
COSMIC Somatic Evidence
Open
Functional Impact & Domains
Functional Domain
Computational Analysis
Pathogenicity Predictions
SpliceAISpliceAI Scores
Window: ±500bp| Effect Type | Score | Position |
|---|---|---|
| Acceptor Loss (AL) | 0.0 | 6 bp |
| Donor Loss (DL) | 0.01 | -83 bp |
| Acceptor Gain (AG) | 0.0 | -85 bp |
| Donor Gain (DG) | 0.0 | 32 bp |
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific)
PVS1 (Not Applied)
According to VCEP guidelines the rule for PVS1 is: 'Very Strong nonsense/frameshift variants introducing PTC ≤ codon 891 in MSH2; or canonical splice ±1/2; or large deletions.' The evidence for this variant shows: it is a missense F23L substitution with no predicted loss-of-function mechanism. Therefore, this criterion is not applied because the variant does not introduce a PTC or affect canonical splice sites.
PS1 (Not Applied)
According to VCEP guidelines the rule for PS1 is: 'Strong A predicted missense substitution that encodes the same amino acid change with a different underlying nucleotide change previously established by this VCEP as Pathogenic.' The evidence for this variant shows: no other nucleotide change encoding F23L has been classified as Pathogenic. Therefore, this criterion is not applied because there is no established pathogenic F23L missense change.
PS2 (Not Applied)
According to VCEP guidelines the rule for PS2 is: 'De novo occurrence with confirmed maternity and paternity points scoring.' The evidence for this variant shows: no de novo data provided. Therefore, this criterion is not applied because there is no de novo evidence.
PS3 (Not Applied)
According to VCEP guidelines the rule for PS3 is: 'Strong calibrated functional assays with odds >18.7; Moderate calibrated assays >4.3; Supporting >2.08.' The evidence for this variant shows: no functional studies have been performed. Therefore, this criterion is not applied because functional assay data are missing.
PS4 (Not Applied)
According to standard ACMG guidelines the rule for PS4 is: 'Increased prevalence of variant in affected individuals compared to controls.' The evidence for this variant shows: no case-control or family enrichment data. Therefore, this criterion is not applied because statistical association data are absent.
PM1 (Not Applied)
According to VCEP guidelines the rule for PM1 is: 'Missense variants in critical functional domains or hotspots.' The evidence for this variant shows: F23L is not located in a known mutational hotspot or critical domain defined by VCEP. Therefore, this criterion is not applied.
PM2 (Not Applied)
According to VCEP guidelines the rule for PM2 (Supporting) is: 'Absent/extremely rare (<1 in 50,000 alleles) in gnomAD v4.' The evidence for this variant shows: MAF=0.0559% overall (1 in 1,789 alleles), above the threshold of 0.002%. Therefore, this criterion is not applied because the allele frequency exceeds the PM2 threshold.
PM3 (Not Applied)
According to VCEP guidelines the rule for PM3 is: 'Detection in trans with a pathogenic variant in recessive disorders with point-based strength.' The evidence for this variant shows: no evidence of trans configuration with a pathogenic allele in a recessive context. Therefore, this criterion is not applied.
PM4 (Not Applied)
According to standard ACMG guidelines the rule for PM4 is: 'Protein length changes due to in-frame indels or stop-loss variants.' The evidence for this variant shows: F23L is a missense substitution with no change in protein length. Therefore, this criterion is not applied.
PM5 (Not Applied)
According to VCEP guidelines the rule for PM5 is: 'Missense change at an amino acid where a different missense variant is classified as Pathogenic or Likely Pathogenic.' The evidence for this variant shows: no other missense variants at residue 23 have been classified as Pathogenic by this VCEP. Therefore, this criterion is not applied.
PM6 (Not Applied)
According to standard ACMG guidelines the rule for PM6 is: 'Assumed de novo without confirmation of paternity/maternity.' The evidence for this variant shows: no de novo assumptions reported. Therefore, this criterion is not applied.
PP1 (Not Applied)
According to VCEP guidelines the rule for PP1 is: 'Co-segregation with disease in multiple affected family members.' The evidence for this variant shows: no segregation data available. Therefore, this criterion is not applied.
PP2 (Not Applied)
According to standard ACMG guidelines the rule for PP2 is: 'Missense variant in a gene with low rate of benign missense.' The evidence for this variant shows: MSH2 has a high rate of clinically relevant missense variants. Therefore, this criterion is not applied.
PP3 (Not Applied)
According to VCEP guidelines the rule for PP3 (Supporting) is: 'Missense variant with HCI prior >0.68 & ≤0.81 or SpliceAI delta ≥0.2.' The evidence for this variant shows: SpliceAI delta=0.01 (no splice effect) and in silico predictors are predominantly benign. Therefore, this criterion is not applied because in silico data do not support pathogenicity.
PP4 (Not Applied)
According to VCEP guidelines the rule for PP4 is: 'Tumor phenotype (MSI-H, loss of MMR) consistent with variant location.' The evidence for this variant shows: no tumor or phenotypic data provided. Therefore, this criterion is not applied.
PP5 (Not Applied)
According to standard ACMG guidelines the rule for PP5 is: 'Reputable source reports variant as pathogenic.' The evidence for this variant shows: no reputable source reports it as pathogenic; instead, multiple labs report benign. Therefore, this criterion is not applied.
BA1 (Not Applied)
According to VCEP guidelines the rule for BA1 is: 'Stand Alone MAF ≥0.001 in gnomAD v4.' The evidence for this variant shows: MAF=0.000559, below 0.001. Therefore, this criterion is not applied.
BS1 (Strong)
According to VCEP guidelines the rule for BS1 is: 'Strong GnomAD v4 Grpmax filtering allele frequency ≥0.0001 and <0.001.' The evidence for this variant shows: MAF=0.000559 (0.0559%), which falls between 0.0001 and 0.001. Therefore, this criterion is applied at Strong strength because the allele frequency is greater than expected for a pathogenic variant.
BS2 (Not Applied)
According to VCEP guidelines the rule for BS2 is: 'Strong co-occurrence in trans with a known pathogenic variant.' The evidence for this variant shows: no co-occurrence data. Therefore, this criterion is not applied.
BS3 (Not Applied)
According to VCEP guidelines the rule for BS3 is: 'Strong calibrated functional assays with odds ≤0.05 or synonymous/intronic with no mRNA aberration.' The evidence for this variant shows: no functional or splicing assay data. Therefore, this criterion is not applied.
BS4 (Not Applied)
According to VCEP guidelines the rule for BS4 is: 'Strong lack of segregation with disease in families.' The evidence for this variant shows: no segregation data. Therefore, this criterion is not applied.
BP1 (Not Applied)
According to standard ACMG guidelines the rule for BP1 is: 'Missense in gene where only truncating variants cause disease.' The evidence for this variant shows: missense variants in MSH2 are known to cause disease. Therefore, this criterion is not applied.
BP2 (Not Applied)
According to standard ACMG guidelines the rule for BP2 is: 'Observed in trans with pathogenic variant in dominant disorder.' The evidence for this variant shows: no such observations. Therefore, this criterion is not applied.
BP3 (Not Applied)
According to standard ACMG guidelines the rule for BP3 is: 'In-frame indel in repetitive region without known function.' The evidence for this variant shows: it is a missense substitution, not an indel. Therefore, this criterion is not applied.
BP4 (Supporting)
According to VCEP guidelines the rule for BP4 is: 'Supporting Missense variant with HCI-prior probability <0.11 OR spliceAI predicts no impact with delta ≤0.1.' The evidence for this variant shows: SpliceAI delta=0.01 and multiple in silico tools predict benign. Therefore, this criterion is applied at Supporting strength because computational data support no impact.
BP5 (Not Applied)
According to VCEP guidelines the rule for BP5 is: 'Supporting multiple tumors with inconsistent MMR expression.' The evidence for this variant shows: no tumor data. Therefore, this criterion is not applied.
BP6 (Supporting)
According to standard ACMG guidelines the rule for BP6 is: 'Supporting Reputable source reports benign outcome without available data.' The evidence for this variant shows: multiple clinical laboratories in ClinVar report benign or likely benign. Therefore, this criterion is applied at Supporting strength because reputable sources classify it as benign.
BP7 (Not Applied)
According to VCEP guidelines the rule for BP7 is: 'Supporting synonymous or intronic variants with no splice impact.' The evidence for this variant shows: it is a missense change, not synonymous/intronic. Therefore, this criterion is not applied.