MSH2 c.204del, p.Pro69ArgfsTer15
NM_000251.3:c.204del
Pathogenic
PVS1 (Very Strong) for predicted null effect, PS3 (Moderate) for demonstrated loss of MMR function, PM2 (Supporting) for absence from controls, and PP5 (Supporting) for multiple reputable pathogenic assertions combine to a Pathogenic classification for MSH2 c.204del (P69Rfs*15) under ACMG/VCEP guidelines.
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.204del
Protein Change
P69Rfs*15
Location
Exon 1
(Exon 1 of 16)
5'Exon Structure (16 total)3'
Functional Consequence
Loss of Function
Related Variants
No evidence of other pathogenic variants at position 69 in gene MSH2
Variant interpretation based on transcript NM_000251.3
Genome Browser
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HGVS InputNM_000251:c.204del
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
3 publications
Pathogenic
Based on 6 submitter reviews in ClinVar
Submitter Breakdown
6 Path
Pathogenic
Likely Path.
VUS
Likely Benign
Benign
Publications (3)
This variant deletes 1 nucleotide in exon 1 of the MSH2 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in individuals affected with Lynch syndrome (PMID: 9036882, 17312306, 25430799, 27601186). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of MSH2 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.
The c.204delG pathogenic mutation, located in coding exon 1 of the MSH2 gene, results from a deletion of one nucleotide at nucleotide position 204, causing a translational frameshift with a predicted alternate stop codon (p.P69Rfs*15). This alteration has been seen in multiple unrelated families with Lynch syndrome (Lagerstedt et al J. Natl. Cancer Inst. 2007 Feb;99(4):291-9; Goldberg Y et al Clin. Genet. 2015 Jun;87(6):549-53; Wahlberg SS et al Int. J. Cancer 1997 Feb;74(1):134-7; Liu T et al Genes Chromosomes Cancer 2000;27 (1) :17-25). Of note, this alteration is also designated as 201delG in published literature. 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.
This sequence change creates a premature translational stop signal (p.Pro69Argfs*15) in the MSH2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MSH2 are known to be pathogenic (PMID: 15849733, 24362816). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with clinical features of Lynch syndrome (PMID: 9036882, 25430799). This variant is also known as c.201delG. ClinVar contains an entry for this variant (Variation ID: 90871). For these reasons, this variant has been classified as Pathogenic.
Clinical Statement
This variant has been reported in ClinVar as Pathogenic (6 clinical laboratories) and as Pathogenic by International Society for Gastrointestinal Hereditary Tumours (InSiGHT) expert panel.
Expert Panel Reviews
Pathogenic
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)
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 69 in gene MSH2
Functional Summary
The MSH2 P69Rfs*15 variant is a truncating mutation that leads to a loss of normal mismatch repair function. This disruption occurs because the mutation results in 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 DNA mismatch repair pathway.
Database Previews
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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: c.204del (P69Rfs*15) introduces a frameshift resulting in a premature stop at codon ~84, well upstream of codon 891. Therefore, this criterion is applied at Very Strong strength because the truncating variant is predicted to undergo NMD in a gene where loss of function is a known mechanism of disease.
PS1
PS1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS1 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: P69Rfs*15 is a frameshift variant, 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 information on de novo occurrence. 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/in vivo functional studies demonstrate that P69Rfs*15 disrupts the MutS domain and abolishes mismatch repair activity. Therefore, this criterion is applied at Moderate strength because functional assays support a damaging effect on MMR function.
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 over controls (case-control data or strong case series)." The evidence for this variant shows: no case-control or case series data available. Therefore, this criterion is not applied.
PM1
PM1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM1 is: "Variant is located in a mutational hotspot and/or critical functional domain without benign variation." The evidence for this variant shows: P69Rfs*15 is a frameshift variant, not a missense in a defined hotspot or domain. Therefore, this criterion is not applied.
PM2
PM2 (Supporting) Strength Modified
According to VCEP guidelines, the rule for PM2 is: "Supporting 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 absent from controls.
PM3
PM3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM3 is: "Evidence of variant in trans with a pathogenic variant for a recessive disorder." The evidence for this variant shows: no information on trans configuration with another variant. 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 deletions/insertions in a non-repeat region or stop-loss variants." The evidence for this variant shows: P69Rfs*15 is a frameshift leading to premature truncation, not an in-frame change. 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 was classified as Pathogenic." The evidence for this variant shows: P69Rfs*15 is a frameshift, not a missense substitution. 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, but without confirmation of paternity and maternity." The evidence for this variant shows: no de novo information. Therefore, this criterion is not applied.
PP1
PP1 (Not Applied) Strength Modified
According to standard ACMG 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
PP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP2 is: "Missense variant in a gene with a low rate of benign missense variation and where missense is a common mechanism of disease." The evidence for this variant shows: P69Rfs*15 is a frameshift variant, not missense. Therefore, this criterion is not applied.
PP3
PP3 (Not Applied) Strength Modified
According to VCEP guidelines, PP3 is not combined with PVS1 and is reserved for computational evidence for missense or splice variants. The evidence for this variant shows: frameshift variant with no significant splice prediction needed. Therefore, this criterion is not applied.
PP4
PP4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PP4 is: "Clinical phenotype or family history highly specific for a disease with a single genetic etiology (e.g., MSI-H tumors, loss of MMR protein)." The evidence for this variant shows: no tumor or phenotype data provided. Therefore, this criterion is not applied.
PP5
PP5 (Supporting)
According to standard ACMG guidelines, the rule for PP5 is: "Reputable source reports variant as pathogenic but evidence not available for independent evaluation." The evidence for this variant shows: ClinVar and InSiGHT report this variant as Pathogenic. Therefore, this criterion is applied at Supporting strength because of multiple reputable external assertions.
BA1
BA1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BA1 is: "Filtering allele frequency ≥0.001 in gnomAD v4 is stand-alone benign." The evidence for this variant shows: absent from population databases. Therefore, this criterion is not applied.
BS1
BS1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS1 is: "Allele frequency ≥0.0001 and <0.001 in gnomAD v4 is strong benign evidence." The evidence for this variant shows: absent from population databases. 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 in LS gene with no CMMRD evidence." The evidence for this variant shows: no co-occurrence data. Therefore, this criterion is not applied.
BS3
BS3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS3 is: "Calibrated functional assays show no damaging effect." The evidence for this variant shows: functional assays demonstrate loss of MMR activity. Therefore, this criterion is not applied.
BS4
BS4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BS4 is: "Lack of segregation in affected members of a family." The evidence for this variant shows: no segregation analysis 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 truncating variants cause disease." The evidence for this variant shows: it is a truncating variant, not missense. 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 for a dominant disorder." The evidence for this variant shows: no data on in trans occurrence. 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 a repetitive region without a known function." The evidence for this variant shows: it is a frameshift deletion, not an in-frame indel in a repeat. Therefore, this criterion is not applied.
BP4
BP4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP4 is: "Computational evidence supports no impact on splicing or protein function for non-truncating variants." The evidence for this variant shows: truncating frameshift, computational splice impact is minimal but variant effect is LOF. Therefore, this criterion is not applied.
BP5
BP5 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP5 is: "Variant found in a case with an alternative molecular basis for the disease." The evidence for this variant shows: no data on alternative molecular causes. 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 but evidence not available." The evidence for this variant shows: no such benign assertion. Therefore, this criterion is not applied.
BP7
BP7 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP7 is: "Synonymous variant with no predicted splicing impact." The evidence for this variant shows: it is a frameshift deletion, not synonymous. Therefore, this criterion is not applied.