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MSH2c.873_876delPathogenic
Print report
Variant interpretation report

MSH2 c.873_876del, p.(Thr292LeufsTer8)

NM_000251.2:c.873_876del NP_000242.1:p.(Thr292LeufsTer8) View identifiers
Classification
Pathogenic

Variant description:

No variant summary was recorded for this case.

Five-step scale from benign to pathogenic. This variant is pathogenic. Select a step to read what it means.

Pathogenic.A pathogenic classification under the recorded framework.

In plain language

Gene-level background from the recorded interpretation.

About MSH2

No gene-level summary was recorded for this case.

LYFE Sciences is an AI system, and it can make mistakes. Criteria may be applied incorrectly, sources may be misread, and a confident-looking classification can still be wrong. Double-check every criterion and its underlying evidence before relying on any call.
01The reasoning

How it was classified

The recorded framework is ClinGen MSH2 VCEP v2.0.0. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.

Recorded applied criteria

The applied criteria and their strengths are shown as assessed under the stated framework.

Pathogenic evidence criteria: 4 Benign evidence criteria: 0
Pathogenic criteria applied · 4
PVS1Very strong
PVS1 · very strong

This frameshift deletion (c.873_876del) in exon 5 of MSH2 introduces a premature termination codon at position ~300 (p.Thr292LeufsTer8), which is ≤ codon 891. Per the InSiGHT VCEP PVS1 rule for MSH2, nonsense/frameshift variants introducing a PTC ≤ codon 891 qualify for PVS1 at Very Strong strength. Loss of function is an established disease mechanism for MSH2 in Lynch syndrome.

PM2Supporting
PM2 · supporting

This variant is absent from gnomAD v2.1 (exomes), gnomAD v4.1 (exomes), and gnomAD-Canada v1.0. Per the VCEP PM2 rule, absence from gnomAD v4 (<1 in 50,000 alleles; AF < 0.00002) qualifies for PM2_Supporting.

PP4Supporting
PP4 · supporting

Kunstmann et al. 2004 (PMID:15217520) reports one patient (0660-6) with a colorectal tumor that was MSI-H, MSH2-negative by IHC (and MSH6-negative, consistent with MSH2 mutation location). This meets the VCEP PP4_Supporting criterion: 1 CRC MSI-H tumor with loss of MMR protein expression consistent with the variant location.

PP5Supporting
PP5 · supporting

Expert panel International Society for Gastrointestinal Hereditary Tumours (InSiGHT) classified as Pathogenic.

Benign criteria applied · 0

No benign criterion marked as applied in the recorded assessment.

Recorded classification: Pathogenic

Richards et.al., 2015 - Combining rules v2.0.0 criteria-combination framework: matched Rule4 (1 Pathogenic.Very Strong + Pathogenic.Supporting >=2) with applied criteria: PVS1 very strong, PM2 supporting, PP4 supporting, PP5 supporting; maps to Pathogenic.

02The sources

Evidence at a glance

Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.

SpliceAI score
0.010 maximum delta

Recorded SpliceAI maximum delta score: 0.010. Refer to the recorded PP3/BP4 rationale for interpretation.

No listed criterion applied SpliceAI ↗
ClinVar submissions
5 reported laboratory submissions

5 Pathogenic. ClinVar API review status: reviewed by expert panel.

Applied · PP5 → ClinVar ↗
Functional evidence
Statement recorded

OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.

No listed criterion applied OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
No matching record reported

This variant has not previously been reported in somatic cancers (COSMIC).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.

Context only
COSMIC ↗Cancer Hotspots ↗
For specialists

Technical detail

ACMG/AMP criteria under ClinGen MSH2 VCEP v2.0.0, with the data and sources behind each one.

28 criteria with recorded statuses: 4 met · 12 not met · 0 not assessed · 12 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic
PVS1PS1PS2PS3PS4PM1PM2PM4PM5PM6PP1PP2PP3PP4PP5PS5
Benign
BA1BS1BS2BS3BS4BP1BP2BP3BP4BP5BP6BP7
Met Not met Not assessed Not applicable

This frameshift deletion (c.873_876del) in MSH2 exon 5 introduces a premature termination codon at position ~300 (p.Thr292LeufsTer8), well before the VCEP codon 891 threshold, meeting PVS1 at Very Strong strength.

The variant is absent from all gnomAD population databases (v2.1, v4.1, Canada v1.0), meeting the VCEP PM2_Supporting threshold of <1 in 50,000 alleles.

One patient with a colorectal tumor demonstrating MSI-H and loss of MSH2 protein expression by IHC (consistent with variant location) has been reported, meeting PP4_Supporting.

ClinVar reports this variant as Pathogenic by the InSiGHT expert panel and by five clinical laboratories (ClinVar ID: 91236).

Under the VCEP combining rules (Rule 4): one Very Strong (PVS1) plus two Supporting (PM2_Supporting + PP4_Supporting) criteria yields a final classification of Pathogenic.

Met · 4

PVS1 Very strongThis frameshift deletion (c.873_876del) in exon 5 of MSH2 introduces a premature termination codon at position ~300 (p.Thr292LeufsTer8), which is ≤ codon 891. Per the InSiGHT VCEP PVS1 rule for MSH2, nonsense/frameshift variants introducing a PTC ≤ codon 891 qualify for PVS1 at Very Strong strength. Loss of function is an established disease mechanism for MSH2 in Lynch syndrome. Details ▾Hide ▴
Evidence considered
  • Frameshift variant introducing premature termination codon at amino acid position ~300
  • well before the codon 891 threshold specified in the VCEP rule
  • Germline loss-of-function is established disease mechanism per InSiGHT CSPEC
  • Variant reported as a pathogenic MSH2 frameshift mutation in Kunstmann et al. 2004 (PMID:15217520)
  • Variant listed in pathogenic MSH2 mutation table in Mangold et al. 2005 (PMID:15849733)
Sources
cspec ↗PMID:15217520 ↗PMID:15849733 ↗
PM2 SupportingThis variant is absent from gnomAD v2.1 (exomes), gnomAD v4.1 (exomes), and gnomAD-Canada v1.0. Per the VCEP PM2 rule, absence from gnomAD v4 (<1 in 50,000 alleles; AF < 0.00002) qualifies for PM2_Supporting. Details ▾Hide ▴
Evidence considered
  • Absent from gnomAD v2.1 (0 alleles)
  • Absent from gnomAD v4.1 (0 alleles)
  • Absent from gnomAD-Canada v1.0 (0 alleles)
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
PP4 SupportingKunstmann et al. 2004 (PMID:15217520) reports one patient (0660-6) with a colorectal tumor that was MSI-H, MSH2-negative by IHC (and MSH6-negative, consistent with MSH2 mutation location). This meets the VCEP PP4_Supporting criterion: 1 CRC MSI-H tumor with loss of MMR protein expression consistent with the variant location. Details ▾Hide ▴
Evidence considered
  • Patient 0660-6 in Kunstmann et al. 2004: CRC with MSI-H
  • MSH2-negative and MSH6-negative IHC
  • consistent with MSH2 variant location
  • Mangold et al. 2005 confirms variant as pathogenic in German HNPCC cohort
Sources
PMID:15217520 ↗PMID:15849733 ↗
PP5 SupportingExpert panel International Society for Gastrointestinal Hereditary Tumours (InSiGHT) classified as Pathogenic. Details ▾Hide ▴
Evidence considered
  • ClinVar expert panel classification
Sources
clinvar ↗

Not met · 12 · evaluated, threshold not reached

PS2 No de novo data are available for this variant. No de novo observations were identified in the literature or ClinVar submissions. Details ▾Hide ▴
Still missing
  • No de novo testing or family trios reported for this variant
PS3 The InSiGHT VCEP functional assay documentation applies to missense, splice-site, and synonymous variants, not frameshift deletions. No calibrated functional assay data exist for this frameshift variant. The OncoKB 'Likely Oncogenic' label is based on predicted loss-of-function from truncation, not experimental functional data. Details ▾Hide ▴
Evidence considered
  • VCEP functional assay framework is restricted to missense
  • splice site
  • and synonymous types
  • No variant-specific or range-based experimental functional data available for this frameshift variant
Still missing
  • No calibrated functional assay applicable to frameshift deletion variants in the MMR VCEP framework
Sources
vcep_functional_assay_svi_documentation_mmr
PP1 No co-segregation data are available for this variant. No pedigrees with Bayes likelihood ratio analysis were identified in the literature. Details ▾Hide ▴
Still missing
  • No co-segregation analysis or Bayes likelihood ratio data available
PP3 The VCEP PP3 rule applies to missense variants (HCI prior >0.68) or non-canonical splice variants (SpliceAI delta ≥0.2). This variant is a frameshift deletion and SpliceAI delta is 0.01. Neither applicable rule is satisfied. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta score = 0.01
  • predicting no significant splice impact
  • HCI prior is not applicable to non-missense variants
Sources
spliceai ↗
BA1 Variant is absent from gnomAD v4.1. Does not meet BA1 threshold of allele frequency ≥0.1% (≥0.001). Details ▾Hide ▴
Evidence considered
  • Absent from gnomAD v4.1
Sources
gnomad_v4 ↗
BS1 Variant is absent from gnomAD v4.1. Does not meet VCEP BS1 threshold of grpmax filtering allele frequency ≥0.0001 and <0.001. Details ▾Hide ▴
Evidence considered
  • Absent from gnomAD v4.1
Sources
gnomad_v4 ↗
BS2 No data on co-occurrence in trans with a known pathogenic MSH2 variant have been reported for this variant. The VCEP BS2 criterion requires observation of co-occurrence in trans with a pathogenic variant in specific clinical contexts. Details ▾Hide ▴
Still missing
  • No co-occurrence in trans data available
BS3 The InSiGHT VCEP BS3 rule requires calibrated functional assay data showing proficient function (functional odds for pathogenicity ≤0.05 for Strong, or >0.05 and ≤0.48 for Supporting). The VCEP functional assay framework applies to missense, splice-site, and synonymous variants, not frameshift deletions. No functional data are available to support normal protein function. Details ▾Hide ▴
Evidence considered
  • VCEP functional assay framework restricted to missense
  • splice site
  • and synonymous types
Sources
vcep_functional_assay_svi_documentation_mmr
BS4 No co-segregation data are available to evaluate lack of segregation with disease. No pedigrees with Bayes likelihood ratio analysis were identified. Details ▾Hide ▴
Still missing
  • No co-segregation data available
BP4 The VCEP BP4 rule applies to missense variants with HCI prior <0.11 or intronic/synonymous variants with SpliceAI delta ≤0.1. This variant is a frameshift deletion and does not fit either BP4 rule category. Details ▾Hide ▴
Evidence considered
  • Frameshift deletion — not eligible for HCI prior or SpliceAI-based BP4 assessment under VCEP rules
BP5 The available clinical data show the opposite of what BP5 requires. Kunstmann et al. 2004 reports the tumor was MSI-H with loss of MSH2 protein expression, which is inconsistent with a benign interpretation. No data showing MSS tumors or retained MMR protein expression in the presence of this variant were identified. Details ▾Hide ▴
Evidence considered
  • Kunstmann et al. 2004: tumor was MSI-H with MSH2-negative IHC — contradictory to BP5 requirement for MSS/retained expression
Sources
PMID:15217520 ↗
BP7 The VCEP BP7 rule applies only to synonymous (silent) or intronic variants at or beyond -21/+7 exon boundaries. This variant is a frameshift deletion in exon 5, not a synonymous or intronic variant. Details ▾Hide ▴

No further detail was recorded.

Not applicable · 12· recorded as not applicable Show reasons ▾Hide reasons ▴
PS1 N/APS1 applies to missense substitutions encoding the same amino acid change via a different nucleotide change, or same splice-site nucleotide alterations. This variant is a frameshift deletion. Details ▾Hide ▴

No further detail was recorded.

PS4 VCEPPS4 is marked as not applicable by the InSiGHT MSH2 VCEP specification. Details ▾Hide ▴

No further detail was recorded.

PM1 VCEPPM1 is marked as not applicable by the InSiGHT MSH2 VCEP specification. Details ▾Hide ▴

No further detail was recorded.

PM4 VCEPPM4 is marked as not applicable by the InSiGHT MSH2 VCEP specification. Details ▾Hide ▴

No further detail was recorded.

PM5 N/AThe VCEP PM5 rule applies only to missense changes at an amino acid residue where a different missense change is classified as Pathogenic/Likely Pathogenic. This is a frameshift deletion, not a missense variant. Details ▾Hide ▴

No further detail was recorded.

PM6 VCEPPM6 is marked as not applicable by the InSiGHT MSH2 VCEP specification. Details ▾Hide ▴

No further detail was recorded.

PP2 VCEPPP2 is marked as not applicable by the InSiGHT MSH2 VCEP specification. Details ▾Hide ▴

No further detail was recorded.

BP1 VCEPBP1 is marked as not applicable by the InSiGHT MSH2 VCEP specification. Details ▾Hide ▴

No further detail was recorded.

BP2 VCEPBP2 is marked as not applicable by the InSiGHT MSH2 VCEP specification. Details ▾Hide ▴

No further detail was recorded.

BP3 VCEPBP3 (in-frame deletions/insertions in repetitive regions without known function) is marked as not applicable by the InSiGHT MSH2 VCEP specification. Details ▾Hide ▴

No further detail was recorded.

BP6 VCEPBP6 is marked as not applicable by the InSiGHT MSH2 VCEP specification. Details ▾Hide ▴

No further detail was recorded.

PS5 N/APS5 is not an established ACMG/AMP criterion. Not applicable. Details ▾Hide ▴

No further detail was recorded.

Identifiers

Gene
MSH2
Transcript
NM_000251.2
Coding (HGVS c.)
NM_000251.2:c.873_876del
Protein (HGVS p.)
NP_000242.1:p.(Thr292LeufsTer8)
GRCh38
chr2:47414345 AACTG>A
GRCh37
chr2:47641484 AACTG>A
ClinVar
91236

Gene diagram

Every interpreted variant in MSH2, mapped onto the exon structure of NM_000251.2. Select a row to find it on the plot.

MSH2NM_000251.2
Fetching transcript structure from UCSC…
gnomAD v4.1 Allele count data not recorded
gnomAD v2.1 Allele count data not recorded
gnomAD-Canada v1.0 Allele count data not recorded

Statements

gnomAD v4.1

Absent from gnomAD v4.1.

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

SpliceAI and Pangolin

SpliceAI acceptor lossat -76 bp
0.000
SpliceAI acceptor gainat -69 bp
0.010
SpliceAI donor lossat +73 bp
0.010
SpliceAI donor gainat -53 bp
0.000
Pangolin splice lossmagnitude shown
-0.120
Pangolin splice gain
0.000

Other predictors

REVEL
Not available
BayesDel
Not available

How the predictions were used

PP3 The VCEP PP3 rule applies to missense variants (HCI prior >0.68) or non-canonical splice variants (SpliceAI delta ≥0.2). This variant is a frameshift deletion and SpliceAI delta is 0.01. Neither applicable rule is satisfied. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta score = 0.01
  • predicting no significant splice impact
  • HCI prior is not applicable to non-missense variants
Sources
spliceai ↗
BP4 The VCEP BP4 rule applies to missense variants with HCI prior <0.11 or intronic/synonymous variants with SpliceAI delta ≤0.1. This variant is a frameshift deletion and does not fit either BP4 rule category. Details ▾Hide ▴
Evidence considered
  • Frameshift deletion — not eligible for HCI prior or SpliceAI-based BP4 assessment under VCEP rules
BP7 The VCEP BP7 rule applies only to synonymous (silent) or intronic variants at or beyond -21/+7 exon boundaries. This variant is a frameshift deletion in exon 5, not a synonymous or intronic variant. Details ▾Hide ▴

No further detail was recorded.

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01).

7 paper records listed. 2 cited in the classification.

Cited in the classification

  • HNPCC: six new pathogenic mutations.
    Kunstmann E et al. · 2004 Jun 24
    Reported c.873_876delGACT (p.L292fsX298) as a novel pathogenic MSH2 frameshift mutation in a German HNPCC family. Patient 0660-6 had colorectal cancer at age 42, tumor was MSI-H with loss of MSH2 and MSH6 protein expression by IHC. Family fulfilled Amsterdam I criteria.
    → PVS1 → PP4 Names this variant
    PMID 15217520 ↗
    Source detail
    c.873_876delGACT [p.L292fsX298]

    Location Abstract; Results (Table 2, page 3); Results and Discussion paragraphs 5-6 (page 4)

    Context Clinical: germline sequencing of MSH2 in patient meeting Amsterdam I criteria. Tumor: MSI testing with BAT-25, BAT-26, D5S346, D17S250, D2S123, BAT-40 panel; IHC for MLH1, MSH2, MSH6 on FFPE tissue.

  • Spectrum and frequencies of mutations in MSH2 and MLH1 identified in 1,721 German families suspected of hereditary nonpolyposis colorectal cancer.
    Mangold E et al. · 2005 Sep 20
    Listed c.873_876delGACT (p.Leu291fs) as a pathogenic MSH2 frameshift mutation identified in the German HNPCC Consortium cohort of 1,721 families. Found in 1 index patient in exon 5.
    → PVS1 → PP4 Names this variant
    PMID 15849733 ↗
    Source detail
    c.873_876delGACT

    Location Table IV: Pathogenic MSH2 mutations (exon 5 section, page 15 of PDF)

Other recorded publications

  • Application of a 5-tiered scheme for standardized classification of 2,360 unique mismatch repair gene variants in the InSiGHT locus-specific database.
    Thompson BA et al. · 2014
    Describes the InSiGHT 5-tiered classification scheme applied to 2,360 MMR gene variants. NM_000251.2:c.873_876del was not individually identified in the searchable full text.
    Does not name this variant
    PMID 24362816 ↗
  • Structure and function of mismatch repair proteins.
    Review of DNA mismatch repair protein structure and function across species. NM_000251.2:c.873_876del was not identified in this paper.
    Does not name this variant
    PMID 10946232 ↗
  • Deficient DNA mismatch repair: a common etiologic factor for colon cancer.
    Review of deficient DNA mismatch repair as an etiologic factor in colon cancer. NM_000251.2:c.873_876del was not identified in this paper.
    Does not name this variant
    PMID 11257106 ↗
  • Mutations associated with HNPCC predisposition -- Update of ICG-HNPCC/INSiGHT mutation database.
    Update of the ICG-HNPCC/InSiGHT mutation database summarizing HNPCC-associated mutations. NM_000251.2:c.873_876del was not individually identified in this paper.
    Does not name this variant
    PMID 15528792 ↗
  • Structural, molecular and cellular functions of MSH2 and MSH6 during DNA mismatch repair, damage signaling and other noncanonical activities.
    Review of structural, molecular and cellular functions of MSH2 and MSH6 during DNA mismatch repair and damage signaling. NM_000251.2:c.873_876del was not identified in this paper.
    Does not name this variant
    PMID 23391514 ↗

Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.

gnomAD v4.1 Captured gnomAD v4.1 source record Open source ↗
gnomAD v2.1 Captured gnomAD v2.1 source record Open source ↗
SpliceAI Lookup Recorded maximum delta 0.010 Open source ↗
ClinVar 5 Pathogenic Open source ↗
COSMIC Captured COSMIC source record Open source ↗
Cancer hotspots Captured Cancer Hotspots source record Open source ↗
OncoKB Captured OncoKB source record Open source ↗
ClinGen CSpec Captured ClinGen CSpec source record Open source ↗

All source links

Statements for reports

The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.

gnomAD v4.1

Absent from gnomAD v4.1.

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

ClinVar

This variant has been reported in ClinVar as Pathogenic (5 clinical laboratories) and as Pathogenic by International Society for Gastrointestinal Hereditary Tumours (InSiGHT) (expert panel). (ClinVarID = 91236)

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01).

Functional

OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.

Somatic

This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.