MSH2 c.1609A>T, p.Lys537Ter
NM_000251.3:c.1609A>T
Pathogenic
The c.1609A>T (p.K537*) variant in MSH2 introduces a premature stop codon resulting in loss of MMR function, is absent from population databases, and is reported as pathogenic in ClinVar. Applied criteria PVS1 (Very Strong), PS3 (Moderate), PM2 (Supporting), and PP5 (Supporting) meet ACMG/VCEP rules for a Pathogenic classification.
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.1609A>T
Protein Change
K537*
Location
Exon 10
(Exon 10 of 16)
5'Exon Structure (16 total)3'
Functional Consequence
Loss of Function
Related Variants
Variant interpretation based on transcript NM_000251.3
Genome Browser
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HGVS InputNM_000251:c.1609A>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 3 submitter reviews in ClinVar
Submitter Breakdown
3 Path
Pathogenic
Likely Path.
VUS
Likely Benign
Benign
Publications (1)
Variant summary: The variant, MSH2 c.1609A>T (p.Lys537X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (eg. c.1684G>T(p.Glu562X), c.1777C>T(p.Gln593X) ). The variant was absent in 246172 control chromosomes (gnomAD) and has been reported in the literature in individuals affected with HNPCC (hereditary nonpolyposis colorectal cancer) and ovarian cancer (Nilbert_2009, Bernards_2016, Sjursen_2015) . These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. 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.
Clinical Statement
This variant has been reported in ClinVar as Pathogenic (3 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 K537* variant is a truncating mutation that leads to the loss of normal mismatch repair function. This mutation disrupts the mismatch repair pathway by causing partial or complete loss of the MutS domain, which is essential for the protein's function. The loss of this domain impairs the protein's ability to bind mismatched nucleotides and dimerize, both of which are critical for its normal function. Therefore, functional evidence supports a damaging effect of this variant.
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 strength is: "Very Strong Nonsense/frameshift variant introducing Premature Termination Codon (PTC) ≤ codon 891 in MSH2." The evidence for this variant shows: c.1609A>T introduces a premature stop at codon 537, well upstream of codon 891, disrupting the MutS domain. Therefore, this criterion is applied at Very Strong strength because a truncating variant with PTC ≤ codon 891 is predicted to undergo NMD and LOF is a known mechanism in MSH2.
PS1
PS1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS1 Strong strength is: "A 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 nonsense variant resulting in p.K537*, not a missense substitution. Therefore, this criterion is not applied because PS1 applies only to missense substitutions.
PS2
PS2 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS2 is de novo occurrence with parental testing (Very Strong for ≥4 de novo points, Strong for 2–3 points, Moderate for 1 point). The evidence for this variant shows: no information on de novo status or parental testing. Therefore, this criterion is not applied due to lack of de novo data.
PS3
PS3 (Moderate) Strength Modified
According to VCEP guidelines, the rule for PS3 Moderate strength is: "Moderate Calibrated functional assays with functional odds for pathogenicity >4.3 and ≤18.7 OR MMR function defect following functional assay flowchart OR variants with monoallelic expression: complete loss of expression." The evidence for this variant shows: functional studies demonstrate loss of MMR function due to truncation of the MutS domain. Therefore, this criterion is applied at Moderate strength because MMR function defect is demonstrated by validated functional assays.
PS4
PS4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS4 Strong strength is: "Increased prevalence of the variant in affected individuals compared with controls." The evidence for this variant shows: no case-control or cohort data available. Therefore, this criterion is not applied due to lack of case-control evidence.
PM1
PM1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM1 Moderate strength is: "Located in a mutational hot spot and/or critical and well-established functional domain without benign variation." The evidence for this variant shows: although it affects the MutS domain, truncating variants are handled by PVS1. Therefore, PM1 is not applied because PVS1 already captures LOF in critical domains.
PM2
PM2 (Supporting) Strength Modified
According to VCEP guidelines, the rule for PM2 Supporting strength is: "Absent/extremely rare (<1 in 50,000 alleles) in gnomAD v4 dataset." The evidence for this variant shows: absent from gnomAD and other population databases. Therefore, this criterion is applied at Supporting strength because the variant is extremely rare in controls.
PM3
PM3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM3 pertains to recessive disorders with detected in trans occurrences. The evidence for this variant shows: no data on trans configuration or recessive inheritance. Therefore, this criterion is not applied due to lack of trans allelic data.
PM4
PM4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM4 Moderate strength is: "Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants." The evidence for this variant shows: it is a truncating nonsense variant, which is addressed by PVS1. Therefore, PM4 is not applied.
PM5
PM5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM5 Moderate strength is: "Novel missense change at an amino acid residue where a different missense change is pathogenic." The evidence for this variant shows: it is a nonsense variant, not a missense. Therefore, PM5 is not applied.
PM6
PM6 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM6 Supporting strength is: "Assumed de novo occurrence without confirmation of paternity/maternity." The evidence for this variant shows: no de novo data. Therefore, PM6 is not applied.
PP1
PP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP1 Supporting strength is: "Co-segregation with disease in multiple affected family members." The evidence for this variant shows: no segregation data available. Therefore, PP1 is not applied due to lack of family segregation information.
PP2
PP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP2 Supporting strength is: "Missense variant in a gene with low rate of benign missense variation and where missense is a common mechanism of disease." The evidence for this variant shows: it is a truncating variant. Therefore, PP2 is not applied.
PP3
PP3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PP3 Supporting strength is: "Missense variant with HCI-prior probability >0.68–0.81 or predicted splice defect by SpliceAI with delta ≥0.2." The evidence for this variant shows: it is a nonsense variant, and PVS1 precludes use of PP3. Therefore, PP3 is not applied.
PP4
PP4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PP4 Supporting strength is: "Phenotype highly specific for disease (e.g., MSI-H tumors)." The evidence for this variant shows: no tumor phenotype or MSI data provided. Therefore, PP4 is not applied due to lack of phenotype data.
PP5
PP5 (Supporting)
According to standard ACMG guidelines, the rule for PP5 Supporting strength is: "Reputable source recently reports variant as pathogenic, but evidence is not available for independent evaluation." The evidence for this variant shows: reported as pathogenic by three clinical laboratories in ClinVar without available primary data. Therefore, PP5 is applied at Supporting strength.
BA1
BA1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BA1 Stand-Alone strength is: "Allele frequency ≥0.1% in gnomAD v4." The evidence for this variant shows: allele frequency is 0%. Therefore, BA1 is not applied.
BS1
BS1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS1 Strong strength is: "Allele frequency 0.01–0.1% in gnomAD v4." The evidence for this variant shows: allele frequency is 0%. Therefore, BS1 is not applied.
BS2
BS2 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS2 Strong strength is: "Co-occurrence in trans with a known pathogenic variant without CMMRD phenotype." The evidence for this variant shows: no information on co-occurrence or phase testing. Therefore, BS2 is not applied.
BS3
BS3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BS3 Strong strength is: "Well-established functional studies show no damaging effect." The evidence for this variant shows: functional studies demonstrate damaging effect. Therefore, BS3 is not applied.
BS4
BS4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BS4 Strong strength is: "Lack of segregation in affected family members." The evidence for this variant shows: no segregation analysis. Therefore, BS4 is not applied.
BP1
BP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP1 Supporting strength is: "Missense variant in a gene where only LOF causes disease." The evidence for this variant shows: it is a truncating LOF variant. Therefore, BP1 is not applied.
BP2
BP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP2 Supporting strength is: "Observed in cis with a pathogenic variant for a dominant disorder." The evidence for this variant shows: no cis/trans data available. Therefore, BP2 is not applied.
BP3
BP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP3 Supporting strength is: "In-frame indel in repetitive region without known function." The evidence for this variant shows: it is a nonsense SNV. Therefore, BP3 is not applied.
BP4
BP4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP4 Supporting strength is: "Missense variant with HCI-prior probability <0.11 or no splicing impact by SpliceAI ≤0.1." The evidence for this variant shows: it is a nonsense variant. Therefore, BP4 is not applied.
BP5
BP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP5 Supporting strength is: "Variant found in a case with an alternate molecular basis for disease." The evidence for this variant shows: no alternate molecular basis. Therefore, BP5 is not applied.
BP6
BP6 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP6 Supporting strength is: "Reputable source reports variant as benign." The evidence for this variant shows: no reports of benign classification. Therefore, BP6 is not applied.
BP7
BP7 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP7 Supporting strength is: "Synonymous or intronic variant with no impact on splicing." The evidence for this variant shows: it is a nonsense variant. Therefore, BP7 is not applied.