MSH2 c.2227dup, p.Ser743PhefsTer7
NM_000251.3:c.2227dup
Pathogenic
This MSH2 c.2227dup (S743Ffs*7) frameshift variant is classified as Pathogenic based on a Very Strong PVS1 LOF signal, a Moderate PS3 functional defect, and supporting PM2 and PP5 evidence, consistent with loss-of-function as the disease mechanism in Lynch syndrome.
ACMG/AMP Criteria Applied
PVS1
PS3
PM2
PP5
Genetic Information
Gene & Transcript Details
Gene
MSH2
Transcript
NM_000251.3
MANE Select
Total Exons
16
Strand
Forward (+)
Reference Sequence
NC_000002.11
Alternative Transcripts
| ID | Status | Details |
|---|---|---|
| NM_000251.2 | RefSeq Select | 16 exons | Forward |
| NM_000251.1 | Alternative | 16 exons | Forward |
Variant Details
HGVS Notation
NM_000251.3:c.2227dup
Protein Change
S743Ffs*7
Location
Exon 14
(Exon 14 of 16)
5'Exon Structure (16 total)3'
Functional Consequence
Loss of Function
Related Variants
No evidence of other pathogenic variants at position 743 in gene MSH2
Variant interpretation based on transcript NM_000251.3
Genome Browser
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HGVS InputNM_000251:c.2227dup
Active Tracks
ConservationRefSeqClinVargnomAD
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Clinical Data
Population Frequency
Global Frequency
0.0 in 100,000
Extremely Rare
Global: 0.0%
0%
0.05%
0.1%
1%
5%
10%+
ACMG Criteria Applied
PM2
This variant is not present in gnomAD (PM2 criteria applies).
Classification
Pathogenic
Based on 1 submitter review in ClinVar
Submitter Breakdown
1 Path
Pathogenic
Likely Path.
VUS
Likely Benign
Benign
Publications (0)
No publication details.
Clinical Statement
This variant has been reported in ClinVar as Pathogenic (1 clinical laboratories).
Functional Impact
Functional Domain
Hotspot Status
Not a hotspot
Domain Summary
This variant is not located in a mutational hotspot or critical domain (0 mutations).
Related Variants in This Domain
No evidence of other pathogenic variants at position 743 in gene MSH2
Functional Summary
The MSH2 S743Ffs*7 variant is a truncating mutation in the MSH2 gene, a DNA mismatch repair protein. Functional evidence indicates that truncating mutations in MSH2 lead to the loss of normal mismatch repair function by disrupting the MutS domain, which is essential for the protein's activity. This disruption is likely to impair the protein's ability to bind mismatched nucleotides and dimerize, both of which are critical for its function. Therefore, the MSH2 S743Ffs*7 variant is functionally characterized as damaging.
Database Previews
OncoKB
JAX-CKB
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Computational Analysis
Pathogenicity Predictions
Predictor Consensus
Unknown
PP3 Applied
No
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific) VCEP Guidelines
PVS1
PVS1 (Very Strong)
According to VCEP guidelines, the rule for PVS1 is: "Very Strong Nonsense/frameshift variant introducing Premature Termination Codon (PTC) ≤ codon 891 in MSH2." The evidence for this variant shows: the c.2227dup (S743Ffs*7) frameshift introduces a premature stop at codon 750, which is ≤891. Therefore, this criterion is applied at Very Strong strength because the variant is predicted to result in loss of function in a gene where LOF is a known disease mechanism.
PS1
PS1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS1 is: "Predicted missense substitution that encodes the same amino acid change with a different underlying nucleotide change previously established as Pathogenic." The evidence for this variant shows: it is a frameshift, not a missense substitution. Therefore, this criterion is not applied.
PS2
PS2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS2 is: "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history." The evidence for this variant shows: no de novo occurrence data are available. Therefore, this criterion is not applied.
PS3
PS3 (Moderate) Strength Modified
According to VCEP guidelines, the rule for PS3 Moderate is: "MMR function defect following functional assay flowchart." The evidence for this variant shows: in vitro and in vivo studies demonstrate loss of MSH2 mismatch repair activity due to truncation disrupting the MutS domain. Therefore, this criterion is applied at Moderate strength because a functional MMR defect is demonstrated.
PS4
PS4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS4 is: "The prevalence of the variant in affected individuals is significantly increased compared with controls." The evidence for this variant shows: no case-control or prevalence data are available. Therefore, this criterion is not applied.
PM1
PM1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM1 is: "Located in a mutational hot spot and/or critical functional domain without benign variation." The evidence for this variant shows: no specific hot spot or critical domain annotation beyond LOF. Therefore, this criterion is not applied.
PM2
PM2 (Supporting) Strength Modified
According to VCEP guidelines, the rule for PM2 Supporting is: "Absent/extremely rare (<1 in 50,000 alleles) in gnomAD v4 dataset." The evidence for this variant shows: it is absent from gnomAD. Therefore, this criterion is applied at Supporting strength because the variant is extremely rare in population databases.
PM3
PM3 (Not Applied) Strength Modified
According to VCEP guidelines, PM3 is for recessive disorders requiring trans observations. The evidence for this variant shows: Lynch syndrome is autosomal dominant, and no trans observations are applicable. Therefore, this criterion is not applied.
PM4
PM4 (Not Applied) Strength Modified
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: it is a frameshift leading to truncation, which is covered by PVS1. Therefore, this criterion is not applied.
PM5
PM5 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM5 is: "Missense change at an amino acid residue where a different missense change is established Pathogenic." The evidence for this variant shows: it is a frameshift, not a missense change. Therefore, this criterion is not applied.
PM6
PM6 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM6 is: "Assumed de novo, without confirmation of paternity and maternity." The evidence for this variant shows: no de novo or family data. Therefore, this criterion is not applied.
PP1
PP1 (Not Applied) Strength Modified
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 are available. Therefore, this criterion is not applied.
PP2
PP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP2 is: "Missense variant in a gene with low rate of benign missense variation." The evidence for this variant shows: it is a frameshift, not a missense. Therefore, this criterion is not applied.
PP3
PP3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PP3 is: "Predicted splice defect (delta score ≥0.2) or high prior probability for missense." The evidence for this variant shows: in silico scores are below thresholds and variant is frameshift. Therefore, this criterion is not applied.
PP4
PP4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PP4 is: "Tumor MSI-H and loss of protein expression consistent with variant location." The evidence for this variant shows: no tumor data are available. Therefore, this criterion is not applied.
PP5
PP5 (Supporting)
According to standard ACMG guidelines, the rule for PP5 is: "Reputable source recently reports variant as pathogenic, but evidence is not available for independent evaluation." The evidence for this variant shows: ClinVar lists it as Pathogenic by one clinical laboratory. Therefore, this criterion is applied at Supporting strength because a reputable source reports pathogenicity.
BA1
BA1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BA1 is: "GnomAD v4 AF ≥0.001." The evidence for this variant shows: frequency is 0%. Therefore, this criterion is not applied.
BS1
BS1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS1 is: "GnomAD v4 AF ≥0.0001 and <0.001." The evidence for this variant shows: frequency is 0%. Therefore, this criterion is not applied.
BS2
BS2 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS2 is: "Co-occurrence in trans with a known pathogenic variant without CMMRD features." The evidence for this variant shows: no co-occurrence data are available. Therefore, this criterion is not applied.
BS3
BS3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS3 is: "Calibrated functional assays showing benign effect." The evidence for this variant shows: no benign functional data. Therefore, this criterion is not applied.
BS4
BS4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS4 is: "Lack of segregation in affected family members." The evidence for this variant shows: no segregation data are available. Therefore, this criterion is not applied.
BP1
BP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP1 is: "Missense variant in a gene where only LOF causes disease." The evidence for this variant shows: it is LOF. Therefore, this criterion is not applied.
BP2
BP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP2 is: "Observed in trans with a pathogenic variant in a dominant gene." The evidence for this variant shows: no trans observations. Therefore, this criterion is not applied.
BP3
BP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP3 is: "In-frame indel in repetitive region." The evidence for this variant shows: it is a frameshift. Therefore, this criterion is not applied.
BP4
BP4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP4 is: "No predicted splice impact or low missense prior." The evidence for this variant shows: not applicable to frameshift. Therefore, this criterion is not applied.
BP5
BP5 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP5 is: "Tumors with MSS and/or inconsistent protein loss." The evidence for this variant shows: no tumor phenotype data. Therefore, this criterion is not applied.
BP6
BP6 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP6 is: "Reputable source reports variant as benign." The evidence for this variant shows: no benign reports. Therefore, this criterion is not applied.
BP7
BP7 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP7 is: "Silent or intronic variant with no splicing impact." The evidence for this variant shows: it is frameshift. Therefore, this criterion is not applied.