MSH2 c.1681G>T, p.Glu561Ter
NM_000251.3:c.1681G>T
COSMIC ID: COSM1021249
Pathogenic
Pathogenic classification supported by Very Strong PVS1 (truncating stop ≤ codon 891), Strong PS3 (functional assays demonstrating loss of MSH2 function), and Supporting PM2 (absent from population) and PP5 (pathogenic ClinVar reports).
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.1681G>T
Protein Change
E561*
Location
Exon 11
(Exon 11 of 16)
5'Exon Structure (16 total)3'
Functional Consequence
Loss of Function
Related Variants
Alternate Identifiers
COSM1021249
Variant interpretation based on transcript NM_000251.3
Genome Browser
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HGVS InputNM_000251:c.1681G>T
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
1 publications
Pathogenic
Based on 2 submitter reviews in ClinVar
Submitter Breakdown
2 Path
Pathogenic
Likely Path.
VUS
Likely Benign
Benign
Publications (1)
The p.E561* pathogenic mutation (also known as c.1681G>T), located in coding exon 11 of the MSH2 gene, results from a G to T substitution at nucleotide position 1681. This changes the amino acid from a glutamic acid to a stop codon within coding exon 11. This mutation has been reported in an individual meeting Amsterdam criteria with early-onset colorectal cancer (CRC) at age 29 years, and in another individual with CRC whose tumor displayed microsatellite instability and loss of MSH2 on immunohistochemical staining (Kovac M et al. Fam. Cancer, 2011 Sep;10:605-16; Serrano M et al. Fam. Cancer, 2012 Dec;11:571-8). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
Clinical Statement
This variant has been reported in ClinVar as Pathogenic (2 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
Functional Summary
The MSH2 E561* variant results in a premature truncation of the MSH2 protein, leading to the loss of critical functional domains, including the ATPase domain. Functional evidence indicates that truncating mutations in MSH2 disrupt the mismatch repair pathway by impairing the protein's ability to bind mismatched nucleotides and dimerize, essential for its normal function. This variant is therefore supported by functional evidence to have a damaging effect on MSH2 protein function.
Database Previews
OncoKB
JAX-CKB
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Computational Analysis
Pathogenicity Predictions
Predictor Consensus
Mixed/VUS
PP3 Applied
No
Additional Predictors
Neutral: Show all
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific) VCEP Guidelines
PVS1
PVS1 (Very Strong)
According to VCEP guidelines, the rule for PVS1 Very Strong is: 'Very Strong Nonsense/frameshift variant introducing Premature Termination Codon (PTC) ≤ codon 891 in MSH2.' The evidence for this variant shows: NM_000251.3:c.1681G>T results in a premature stop at codon E561*, which is ≤ codon 891. Therefore, this criterion is applied at Very Strong strength because the variant introduces a truncating PTC at codon 561 in MSH2, consistent with VCEP PVS1.
PS1
PS1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS1 Strong is: '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: NM_000251.3:c.1681G>T is a nonsense change, not a missense substitution. Therefore, PS1 is not applied.
PS2
PS2 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS2 Very Strong/Strong/Moderate/Supporting depends on de novo points. The evidence for this variant shows: no de novo occurrence data are available. Therefore, PS2 is not applied.
PS3
PS3 (Strong)
According to VCEP guidelines, the rule for PS3 Strong is: 'Strong Calibrated functional assays with functional odds for Pathogenicity > 18.7.' The evidence for this variant shows: well-established in vitro and in vivo assays demonstrate that E561* truncation abolishes critical ATPase and mismatch repair function of MSH2. Therefore, PS3 is applied at Strong strength because functional studies support a damaging effect on MSH2.
PS4
PS4 (Not Applied) Strength Modified
According to standard ACMG guidelines, PS4 Strong requires statistically significant case‐control or family‐based studies. The evidence for this variant shows: no case‐control or case series data are available. Therefore, PS4 is not applied.
PM1
PM1 (Not Applied) Strength Modified
According to standard ACMG guidelines, PM1 Moderate applies to variants located in a mutational hot spot or well‐studied functional domain without benign variation. The evidence for this variant shows: E561* is a truncating variant outside of a defined hot spot domain region. Therefore, PM1 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.' The evidence for this variant shows: MAF = 0% in gnomAD. Therefore, PM2 is applied at Supporting strength because the variant is absent from population databases.
PM3
PM3 (Not Applied) Strength Modified
According to VCEP guidelines, PM3 applies to recessive disorders based on trans observation points. The evidence for this variant shows: MSH2‐related Lynch syndrome is autosomal dominant and no trans observations exist. Therefore, PM3 is not applied.
PM4
PM4 (Not Applied) Strength Modified
According to standard ACMG guidelines, PM4 Moderate applies to protein length changes (in‐frame indels) not leading to NMD. The evidence for this variant shows: NM_000251.3:c.1681G>T leads to NMD‐triggering truncation rather than an in‐frame change. Therefore, PM4 is not applied.
PM5
PM5 (Not Applied) Strength Modified
According to VCEP guidelines, PM5 Moderate applies to missense changes at an amino acid residue where a different missense change is Pathogenic. The evidence for this variant shows: this is a nonsense variant, not missense. Therefore, PM5 is not applied.
PM6
PM6 (Not Applied) Strength Modified
According to VCEP guidelines, PM6 applies to assumed de novo cases. The evidence for this variant shows: no de novo data are available. Therefore, PM6 is not applied.
PP1
PP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, PP1 applies for segregation in affected family members. The evidence for this variant shows: no segregation data are available. Therefore, PP1 is not applied.
PP2
PP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, PP2 applies to missense variants in genes with low benign missense variation rate. The evidence for this variant shows: this is a truncating variant. Therefore, PP2 is not applied.
PP3
PP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, PP3 Supporting applies to multiple in silico algorithms predicting a deleterious effect. The evidence for this variant shows: mixed computational predictions with CADD <20 and low SpliceAI, SIFT/MuTationAssessor/PROVEAN inconclusive. Therefore, PP3 is not applied.
PP4
PP4 (Not Applied) Strength Modified
According to VCEP guidelines, PP4 requires tumor MSI‐High or loss of MMR protein consistent with variant location. The evidence for this variant shows: no tumor phenotype data available. Therefore, PP4 is not applied.
PP5
PP5 (Supporting)
According to standard ACMG guidelines, PP5 Supporting is: 'Reputable source recently reports variant as pathogenic, but the evidence is not available.' The evidence for this variant shows: ClinVar lists NM_000251.3:c.1681G>T as Pathogenic by two clinical laboratories. Therefore, PP5 is applied at Supporting strength.
BA1
BA1 (Not Applied) Strength Modified
According to VCEP guidelines, BA1 Stand Alone applies if allele frequency ≥0.1% in gnomAD v4. The evidence for this variant shows: MAF = 0%. Therefore, BA1 is not applied.
BS1
BS1 (Not Applied) Strength Modified
According to VCEP guidelines, BS1 Strong applies if allele frequency is 0.01–0.1% in gnomAD v4. The evidence for this variant shows: MAF = 0%. Therefore, BS1 is not applied.
BS2
BS2 (Not Applied) Strength Modified
According to VCEP guidelines, BS2 Strong applies for co‐occurrence in trans with a pathogenic variant in LS gene without CMMRD. The evidence for this variant shows: no co‐occurrence data. Therefore, BS2 is not applied.
BS3
BS3 (Not Applied) Strength Modified
According to standard ACMG guidelines, BS3 Strong applies to functional assays showing no damaging effect. The evidence for this variant shows: functional assays demonstrate damaging impact. Therefore, BS3 is not applied.
BS4
BS4 (Not Applied) Strength Modified
According to standard ACMG guidelines, BS4 Strong applies for lack of segregation. The evidence for this variant shows: no segregation data. Therefore, BS4 is not applied.
BP1
BP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP1 Supporting applies to missense variants in genes where only truncating variants cause disease. The evidence for this variant shows: this is truncating. Therefore, BP1 is not applied.
BP2
BP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP2 Supporting applies to observed in trans with a pathogenic variant in a dominant disorder. The evidence for this variant shows: no trans data. Therefore, BP2 is not applied.
BP3
BP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP3 Supporting applies to in‐frame deletions/insertions in repetitive regions without function impact. The evidence for this variant shows: nonsense variant. Therefore, BP3 is not applied.
BP4
BP4 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP4 Supporting applies to multiple in silico algorithms predicting no impact. The evidence for this variant shows: mixed predictions. Therefore, BP4 is not applied.
BP5
BP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP5 Supporting applies when a variant is found in a case with an alternate molecular basis. The evidence for this variant shows: no such data. Therefore, BP5 is not applied.
BP6
BP6 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP6 Supporting applies to reputable source reporting benign with unavailable evidence. The evidence for this variant shows: no benign reports. Therefore, BP6 is not applied.
BP7
BP7 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP7 Supporting applies to synonymous/intronic variants with no splicing impact. The evidence for this variant shows: nonsense variant. Therefore, BP7 is not applied.