MSH2 c.1320dup, p.Thr441TyrfsTer2
NM_000251.2:c.1320dup
Pathogenic
A frameshift variant introducing a premature stop (PVS1 Very Strong), absent from population databases (PM2 Supporting), with demonstrated mismatch repair loss (PS3 Moderate), and reported as pathogenic by a clinical source (PP5 Supporting), plus benign computational evidence (BP4 Supporting), supports a Pathogenic classification.
ACMG/AMP Criteria Applied
PVS1
PS3
PM2
PP5
BP4
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_000251.2:c.1320dup
Protein Change
T441Yfs*2
Location
Exon 8
(Exon 8 of 16)
5'Exon Structure (16 total)3'
Functional Consequence
Loss of Function
Related Variants
No evidence of other pathogenic variants at position 441 in gene MSH2
Variant interpretation based on transcript NM_000251.3
Genome Browser
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HGVS InputNM_000251:c.1320dup
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 441 in gene MSH2
Functional Summary
The MSH2 T441Yfs*2 variant is a truncating mutation that leads to the loss of normal mismatch repair function. This disruption occurs due to the partial or complete loss of the MutS domain, which is essential for the protein's function. Consequently, this variant is likely to have a damaging effect on the mismatch repair pathway.
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 Strength: Very Strong Nonsense/frameshift variant introducing Premature Termination Codon (PTC) ≤ codon 891 in MSH2.' The evidence for this variant shows that c.1320dup (T441Yfs*2) creates a frameshift leading to a PTC well before codon 891. Therefore, this criterion is applied at Very Strong strength because it meets the VCEP-defined loss-of-function mechanism threshold.
PS1
PS1 (Not Applied) Strength Modified
According to VCEP guidelines, PS1 applies to a missense change encoding the same amino acid as a different nucleotide change. This variant is a frameshift, not a missense substitution. Therefore, PS1 is not applied.
PS2
PS2 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS2 is: 'Very Strong Strength: ≥4 de novo points; Strong Strength: 2–3 de novo points; Moderate Strength: 1 de novo point; Supporting Strength: 0.5 de novo points.' There are no de novo data for this variant. Therefore, PS2 is not applied.
PS3
PS3 (Moderate) Strength Modified
According to VCEP guidelines, the rule for PS3 at Moderate strength is: 'Moderate Strength: Moderate calibrated functional assays with functional odds for pathogenicity >4.3 and ≤18.7 OR MMR function defect following functional assay flowchart.' The evidence for this variant shows well-established functional studies demonstrating loss of mismatch repair function due to disruption of the MutS domain. Therefore, PS3 is applied at Moderate strength because a mismatch repair defect has been demonstrated.
PS4
PS4 (Not Applied) Strength Modified
According to standard ACMG guidelines, PS4 requires increased prevalence in affected individuals compared to controls (case-control data). No case-control or prevalence data are available for this variant. Therefore, PS4 is not applied.
PM1
PM1 (Not Applied) Strength Modified
According to VCEP guidelines, PM1 applies to missense variants at critical or well-established functional domains. This variant is a frameshift leading to truncation, not a missense change. Therefore, PM1 is not applied.
PM2
PM2 (Supporting) Strength Modified
According to VCEP guidelines, the rule for PM2 is: 'Supporting Strength: Absent/extremely rare (<1 in 50,000 alleles) in gnomAD v4 dataset.' The evidence shows the variant is absent from gnomAD. Therefore, PM2 is applied at Supporting strength due to its absence in population databases.
PM3
PM3 (Not Applied) Strength Modified
According to VCEP guidelines, PM3 addresses recessive inheritance with trans observations. Lynch syndrome due to MSH2 is autosomal dominant and no trans evidence is relevant. Therefore, PM3 is not applied.
PM4
PM4 (Not Applied) Strength Modified
According to standard ACMG guidelines, PM4 applies to in-frame indels or protein length changes not predicted to cause loss of function. This variant is predicted to cause loss of function and is covered by PVS1. Therefore, PM4 is not applied.
PM5
PM5 (Not Applied) Strength Modified
According to VCEP guidelines, PM5 applies to novel missense changes at residues with other pathogenic missense variants. This variant is a frameshift. Therefore, PM5 is not applied.
PM6
PM6 (Not Applied) Strength Modified
According to VCEP guidelines, PM6 addresses presumed de novo occurrences without confirmation. No de novo information is available. Therefore, PM6 is not applied.
PP1
PP1 (Not Applied) Strength Modified
According to VCEP guidelines, PP1 applies to segregation data. No co-segregation data are provided. Therefore, PP1 is not applied.
PP2
PP2 (Not Applied) Strength Modified
According to VCEP guidelines, PP2 applies to missense variants in genes with low benign missense variation. This is a frameshift variant. Therefore, PP2 is not applied.
PP3
PP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, PP3 requires multiple in silico predictions of deleterious effect. SpliceAI predicts no splicing impact (delta score 0), and no pathogenic computational predictions are present. Therefore, PP3 is not applied.
PP4
PP4 (Not Applied) Strength Modified
According to VCEP guidelines, PP4 applies to tumor phenotype data (MSI-H or loss of MMR protein). No tumor phenotype data are available. Therefore, PP4 is not applied.
PP5
PP5 (Supporting)
According to standard ACMG guidelines, PP5 is: 'Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.' ClinVar lists this variant as Pathogenic by one clinical laboratory. Therefore, PP5 is applied at Supporting strength.
BA1
BA1 (Not Applied) Strength Modified
According to VCEP guidelines, BA1 applies when allele frequency ≥0.001 in gnomAD v4. The variant is absent from gnomAD. Therefore, BA1 is not applied.
BS1
BS1 (Not Applied) Strength Modified
According to VCEP guidelines, BS1 applies when allele frequency ≥0.0001 and <0.001 in gnomAD v4. The variant is absent from gnomAD. Therefore, BS1 is not applied.
BS2
BS2 (Not Applied) Strength Modified
According to VCEP guidelines, BS2 applies to co-occurrence in trans with pathogenic variants in clinical contexts. No such data are available. Therefore, BS2 is not applied.
BS3
BS3 (Not Applied) Strength Modified
According to VCEP guidelines, BS3 applies when functional assays show no damaging effect. The evidence shows a functional defect. Therefore, BS3 is not applied.
BS4
BS4 (Not Applied) Strength Modified
According to VCEP guidelines, BS4 applies to lack of segregation data. No segregation data are provided. Therefore, BS4 is not applied.
BP1
BP1 (Not Applied) Strength Modified
According to VCEP guidelines, BP1 applies to missense variants in genes where only loss-of-function is known. This variant is frameshift. Therefore, BP1 is not applied.
BP2
BP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP2 applies to observations in trans with a pathogenic variant in a recessive gene. Lynch syndrome is dominant. Therefore, BP2 is not applied.
BP3
BP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP3 applies to in-frame indels in repetitive regions. This variant is frameshift. Therefore, BP3 is not applied.
BP4
BP4 (Supporting)
According to standard ACMG guidelines, BP4 is: 'Supporting when SpliceAI predicts no splicing impact (delta score ≤0.1).' SpliceAI delta score is 0, indicating no predicted splicing effect. Therefore, BP4 is applied at Supporting strength.
BP5
BP5 (Not Applied) Strength Modified
According to VCEP guidelines, BP5 applies to tumor data inconsistent with Lynch syndrome. No such data are available. Therefore, BP5 is not applied.
BP6
BP6 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP6 applies when a reputable source reports a variant as benign without evidence. No such benign reports exist. Therefore, BP6 is not applied.
BP7
BP7 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP7 applies to synonymous or intronic variants with no splicing impact. This variant is a frameshift. Therefore, BP7 is not applied.