MSH2c.2001_2002delUncertain significance

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Variant interpretation report

MSH2 c.2001_2002del, p.(Thr668TrpfsTer7)

NM_000251.3:c.2001_2002del NP_000242.1:p.(Thr668TrpfsTer7) View identifiers

Classification

Uncertain significance

Variant description:

No variant summary was recorded for this case.

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

Uncertain.The recorded classification is uncertain significance.

In plain language

Gene-level background from the recorded interpretation.

About MSH2

No gene-level summary was recorded for this case.

Key facts

Evidence used: 1 very strong (pathogenic) · 1 supporting (pathogenic)
Expert rules: ClinGen MSH2 VCEP v2.0
Pipeline record: 28 Jul 2026 · version 7.0.4

Evidence considered

View criteria

Applied evidence criteria

PVS1 (very strong): NM_000251.3:c.2001_2002del is a 2-bp deletion in exon 12 of MSH2 causing a frameshift at codon 668 (p.Thr668TrpfsTer7) that introduces a premature termination codon at position 674, well before the InSiGHT VCEP cutoff of codon 891 for PVS1_VeryStrong. The PTC is located >50 nucleotides upstream of the last exon-exon junction and is predicted to trigger nonsense-mediated decay, supporting complete loss of function.
PM2 (supporting): NM_000251.3:c.2001_2002del is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0. The allele frequency is below the InSiGHT VCEP threshold of <0.00002 (<1 in 50,000 alleles) for PM2_Supporting.

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. 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: 2 Benign evidence criteria: 0

Pathogenic criteria applied · 2

PVS1Very strong

PVS1 · very strong

NM_000251.3:c.2001_2002del is a 2-bp deletion in exon 12 of MSH2 causing a frameshift at codon 668 (p.Thr668TrpfsTer7) that introduces a premature termination codon at position 674, well before the InSiGHT VCEP cutoff of codon 891 for PVS1_VeryStrong. The PTC is located >50 nucleotides upstream of the last exon-exon junction and is predicted to trigger nonsense-mediated decay, supporting complete loss of function.

PM2Supporting

PM2 · supporting

NM_000251.3:c.2001_2002del is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0. The allele frequency is below the InSiGHT VCEP threshold of <0.00002 (<1 in 50,000 alleles) for PM2_Supporting.

Benign criteria applied · 0

No benign criterion marked as applied in the recorded assessment.

Recorded classification: Uncertain significance

ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for MSH2 Version 2.0 v2.0 criteria-combination framework was evaluated deterministically with applied criteria: PVS1 very strong, PM2 supporting; no rule matched the adjudicated criteria.

02The sources

Evidence at a glance

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

gnomAD v4.1

gnomAD v2.1

Population frequency

Not recorded

gnomAD v4.1 allele counts were not recorded for this variant.

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

Applied · PM2 →

gnomAD v4.1 ↗gnomAD v2.1 ↗gnomAD-Canada ↗

SpliceAI score

0.070 maximum delta

Recorded SpliceAI maximum delta score: 0.070. Refer to the recorded PP3/BP4 rationale for interpretation.

No listed criterion applied SpliceAI ↗

ClinVar submissions

Not recorded

A ClinVar laboratory submission summary was not recorded.

Context only 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, with the data and sources behind each one.

28 criteria with recorded statuses: 2 met · 13 not met · 0 not assessed · 13 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic

PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 PS5

Benign

BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7

Met Not met Not assessed Not applicable

NM_000251.3:c.2001_2002del is a 2-bp deletion in exon 12 of MSH2 that causes a frameshift (p.Thr668TrpfsTer7) and introduces a premature termination codon at position 674, well before the InSiGHT VCEP PVS1_VeryStrong cutoff of codon 891.

The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada, meeting PM2_Supporting under InSiGHT VCEP criteria (allele frequency <0.00002).

The variant is absent from ClinVar and has not been reported in COSMIC; no published case reports or functional studies specific to this variant were identified in the five publications reviewed.

Applying the InSiGHT MMR VCEP v2.0 combining rules: one Pathogenic Very Strong criterion (PVS1) plus one Pathogenic Supporting criterion (PM2) meets Rule 10 for Likely Pathogenic (1 Very Strong + 1 Moderate, but PM2 is only Supporting in this VCEP, so the classification defaults to Rule 10: 1 Very Strong + 1 Moderate = Likely Pathogenic; however PM2_Supporting alone with PVS1 does not reach a second moderate — the classification resolves under Rule 1: ≥1 Very Strong = Pathogenic).

Met · 2

PVS1 Very strongNM_000251.3:c.2001_2002del is a 2-bp deletion in exon 12 of MSH2 causing a frameshift at codon 668 (p.Thr668TrpfsTer7) that introduces a premature termination codon at position 674, well before the InSiGHT VCEP cutoff of codon 891 for PVS1_VeryStrong. The PTC is located >50 nucleotides upstream of the last exon-exon junction and is predicted to trigger nonsense-mediated decay, supporting complete loss of function. Details ▾Hide ▴

Evidence considered

Frameshift variant introduces PTC at codon 674 (NP_000242.1:p.Thr668TrpfsTer7)
PTC at codon 674 ≤ VCEP cutoff of codon 891 for MSH2 PVS1_VeryStrong
NMD predicted: PTC located >50 nucleotides upstream of last exon-exon junction
Loss of function is an established disease mechanism in MSH2 per InSiGHT VCEP

Sources

cspec ↗pvs1_gene_contextgnomad_v2 ↗gnomad_v4 ↗

PM2 SupportingNM_000251.3:c.2001_2002del is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0. The allele frequency is below the InSiGHT VCEP threshold of <0.00002 (<1 in 50,000 alleles) 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)
Allele frequency below VCEP threshold of 0.00002

Sources

gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

Not met · 13 · evaluated, threshold not reached

PS2 No de novo observations have been reported for this variant. The case materials contain no proband or family data, and no published de novo reports were identified in the literature reviewed. Details ▾Hide ▴

Still missing

No proband or family history provided in case materials
No de novo reports identified in literature

PS3 This is a frameshift null variant; the InSiGHT VCEP calibrated functional assays (CIMRA, saturation mutagenesis) are designed for missense, splice site, and synonymous variants. No calibrated functional assay data exists for frameshift variants in MSH2 under this VCEP. OncoKB annotation of Likely Loss-of-function is an in silico inference, not experimental functional evidence meeting PS3 calibration thresholds. Details ▾Hide ▴

Evidence considered

VCEP functional assay documentation targets missense
splice site
and synonymous variants only
Frameshift null variants are not evaluated by calibrated MMR functional assays
OncoKB Likely Loss-of-function is a curated inference
not calibrated experimental data

Sources

vcep_functional_assay_svi_documentation_mmroncokb ↗

PP1 No co-segregation data available. The case materials contain no pedigree information, and no published co-segregation analyses for this variant were identified. Details ▾Hide ▴

Still missing

No pedigree or co-segregation data provided

PP4 No tumor MSI/IHC data provided. The InSiGHT VCEP requires MSI-H tumors with loss of MMR protein expression consistent with variant location to apply PP4. The case materials contain no patient phenotype or tumor testing results. Details ▾Hide ▴

Still missing

No tumor MSI or IHC data provided

PP5 This variant is absent from ClinVar. The InSiGHT VCEP marks PP5 as not applicable for this framework. Even if the global override were considered, there is no ClinVar classification or 3-star expert panel review to cite. Details ▾Hide ▴

Evidence considered

Variant not present in ClinVar

Sources

clinvar ↗

BA1 NM_000251.3:c.2001_2002del is absent from gnomAD v2.1, v4.1, and gnomAD-Canada. The allele frequency is 0, well below the InSiGHT VCEP BA1 threshold of ≥0.001 (0.1%). Details ▾Hide ▴

Evidence considered

Absent from all gnomAD populations
Allele frequency 0
below BA1 threshold of 0.001

Sources

gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

BS1 NM_000251.3:c.2001_2002del is absent from gnomAD v4.1. The allele frequency is 0, below the InSiGHT VCEP BS1 threshold of ≥0.0001 (0.01%). Details ▾Hide ▴

Evidence considered

Absent from gnomAD v4.1
Allele frequency 0
below BS1 threshold of 0.0001

Sources

gnomad_v2 ↗gnomad_v4 ↗

BS2 No evidence of co-occurrence in trans with a known pathogenic MSH2 variant in a patient without CMMRD. The case materials contain no co-occurrence data. Details ▾Hide ▴

Still missing

No co-occurrence data available

BS3 The InSiGHT VCEP BS3 calibrated functional assays target missense, splice site, and synonymous variants. This frameshift null variant is not evaluated by these assays. No functional evidence demonstrating normal protein function has been identified. Details ▾Hide ▴

Evidence considered

VCEP functional assays do not apply to frameshift variants

Sources

vcep_functional_assay_svi_documentation_mmr

BS4 No co-segregation data showing lack of segregation with disease. The case materials contain no pedigree information. Details ▾Hide ▴

Still missing

No pedigree or segregation data available

BP5 No evidence of an alternate molecular basis for disease. The case materials do not identify any other pathogenic variant or alternative diagnosis that would explain the phenotype. Details ▾Hide ▴

Still missing

No alternate molecular basis identified

BP6 This variant is absent from ClinVar. The InSiGHT VCEP marks BP6 as not applicable. Even if the global override were considered, there is no ClinVar benign classification to cite. Details ▾Hide ▴

Evidence considered

Variant not present in ClinVar

Sources

clinvar ↗

PS5 No case-control evidence or proband enrichment data available for this variant. The variant is absent from ClinVar and COSMIC, and no published case series were identified. Details ▾Hide ▴

Still missing

No case reports or case series identified

Not applicable · 13· recorded as not applicable Show reasons ▾Hide reasons ▴

PS1 N/APS1 applies to missense substitutions encoding the same amino acid change as a known pathogenic variant, or splice variants at the same non-canonical nucleotide. This is a frameshift deletion and does not meet the variant-type requirements for PS1. Details ▾Hide ▴

No further detail was recorded.

PS4 VCEPThe InSiGHT VCEP does not utilize PS4 for MMR variant classification; tumor IHC data is addressed through PP4 instead. Details ▾Hide ▴

Sources

cspec ↗

PM1 VCEPThe InSiGHT VCEP explicitly states PM1 is not applicable for MMR genes: 'There are no recognized mutational hot spots that could be used for classification purposes. While there are functional domains in the MMR genes, the distribution of pathogenic variants is generalized over all the domains.' Details ▾Hide ▴

Sources

cspec ↗

PM4 VCEPThe InSiGHT VCEP does not use PM4: 'Protein length change from an in-frame variant is not used due to lack of evidence.' This variant is also an out-of-frame frameshift, not an in-frame deletion. Details ▾Hide ▴

Sources

cspec ↗

PM5 N/APM5 applies to missense variants at a residue where a different pathogenic missense change has been classified. This variant is a frameshift deletion and does not meet the variant-type requirements for PM5. Details ▾Hide ▴

No further detail was recorded.

PM6 VCEPThe InSiGHT VCEP marks PM6 as not applicable; presumed de novo without confirmed parentage is not used for MMR variant classification under this framework. Details ▾Hide ▴

Sources

cspec ↗

PP2 VCEPThe InSiGHT VCEP does not apply PP2: 'Missense variant in a gene with low rate of benign missense changes does not apply.' This variant is also a frameshift, not a missense substitution. Details ▾Hide ▴

Sources

cspec ↗

PP3 N/APP3 in the InSiGHT VCEP applies to missense variants via HCI prior probability (>0.68) or to splice variants via SpliceAI delta score (≥0.2). This is a frameshift deletion. HCI prior is not available for non-substitution variants, and SpliceAI predicts no significant splice impact (max delta = 0.07). Details ▾Hide ▴

Evidence considered

HCI prior not applicable to frameshift variant
SpliceAI max delta score 0.07
below VCEP threshold of 0.2

Sources

spliceai ↗vcep_hci_priors_msh2

BP1 VCEPThe InSiGHT VCEP does not apply BP1: 'Missense variant in a gene where only loss of function causes disease is not applicable.' This is also a frameshift variant, not a missense substitution. Details ▾Hide ▴

Sources

cspec ↗

BP2 VCEPThe InSiGHT VCEP replaces BP2 with BS2 for MMR variant classification. BP2 is not used under this framework. Details ▾Hide ▴

Sources

cspec ↗

BP3 VCEPThe InSiGHT VCEP does not use BP3: 'In-frame deletions/insertions in a repetitive region without a known function is not used.' This variant is also an out-of-frame frameshift, not an in-frame alteration. Details ▾Hide ▴

Sources

cspec ↗

BP4 N/ABP4 in the InSiGHT VCEP applies to missense variants via HCI prior (<0.11) or to synonymous/intronic variants via SpliceAI (≤0.1). This is a frameshift deletion; HCI prior is not available, and the variant type does not fall under the BP4 criteria. Details ▾Hide ▴

Evidence considered

HCI prior not applicable to frameshift variant
SpliceAI max delta 0.07
but BP4 for SpliceAI only applies to synonymous/intronic variants

Sources

vcep_hci_priors_msh2spliceai ↗

BP7 N/ABP7 in the InSiGHT VCEP applies to synonymous or intronic variants at or beyond -21/+7. This is a frameshift deletion and does not meet the variant-type requirements. Details ▾Hide ▴

Sources

cspec ↗

Identifiers

Gene: MSH2
Transcript: NM_000251.3
Coding (HGVS c.): NM_000251.3:c.2001_2002del
Protein (HGVS p.): NP_000242.1:p.(Thr668TrpfsTer7)
GRCh38: chr2:47475265 TTA>T
GRCh37: chr2:47702404 TTA>T

Gene diagram

Every interpreted variant in MSH2, mapped onto the exon structure of NM_000251.3. Select a row to find it on the plot.

MSH2NM_000251.3

Fetching transcript structure from UCSC…

Exons

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Transcript span

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Strand

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Variants mapped

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Source

UCSC ncbiRefSeqCurated

All variants in MSH2 — Select a row to find it on the plot; use the link to open its page.

	Protein	Location	Classification	Link

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 -265 bp

0.000

SpliceAI acceptor gainat -231 bp

0.000

SpliceAI donor lossat +5 bp

0.000

SpliceAI donor gainat +36 bp

0.070

Pangolin splice lossmagnitude shown

-0.070

Pangolin splice gain

0.020

Other predictors

REVEL: Not available
BayesDel: Not available

How the predictions were used

Evidence considered

HCI prior not applicable to frameshift variant
SpliceAI max delta score 0.07
below VCEP threshold of 0.2

Sources

spliceai ↗vcep_hci_priors_msh2

Evidence considered

HCI prior not applicable to frameshift variant
SpliceAI max delta 0.07
but BP4 for SpliceAI only applies to synonymous/intronic variants

Sources

vcep_hci_priors_msh2spliceai ↗

BP7 N/ABP7 in the InSiGHT VCEP applies to synonymous or intronic variants at or beyond -21/+7. This is a frameshift deletion and does not meet the variant-type requirements. Details ▾Hide ▴

Sources

cspec ↗

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.07).

5 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata. None of the listed paper records explicitly indicates that the variant is named.

Recorded publications

Structure and function of mismatch repair proteins.

Reviews the crystal structures of E. coli MutH, MutL, and MutS mismatch repair proteins. NM_000251.3:c.2001_2002del was not identified in this paper.
Does not name this variant
PMID 10946232 ↗
Deficient DNA mismatch repair: a common etiologic factor for colon cancer.

Reviews the genetics of HNPCC and deficient DNA mismatch repair. Discusses MSH2, MLH1, and MSH6 mutation spectra at the gene level. NM_000251.3:c.2001_2002del 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.

Updates the ICG-HNPCC/INSiGHT mutation database with 448 MMR gene mutations across 748 families. Discusses exonic distribution of MSH2 mutations and mutation types (frameshift, nonsense, missense). NM_000251.3:c.2001_2002del was not 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.

Reviews structural, molecular, and cellular functions of MSH2 and MSH6 during DNA mismatch repair, damage signaling, and noncanonical activities. NM_000251.3:c.2001_2002del was not identified in this paper.
Does not name this variant
PMID 23391514 ↗
Application of a 5-tiered scheme for standardized classification of 2,360 unique mismatch repair gene variants in the InSiGHT locus-specific database.

Describes the 5-tiered InSiGHT classification scheme applied to 2,360 unique MMR gene variants. Discusses classification methodology and criteria integration. NM_000251.3:c.2001_2002del was not identified in this paper.
Does not name this variant
PMID 24362816 ↗

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 0.070 Open source ↗

ClinVar Captured ClinVar source record 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 is absent from ClinVar.

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.07).

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.