Variant classification summary

NM_000251.3:c.2001_2002del

MSH2 · NP_000242.1:p.(Thr668TrpfsTer7) · NM_000251.3

GRCh37: chr2:47702404 TTA>T · GRCh38: chr2:47475265 TTA>T

Gene: MSH2 Transcript: NM_000251.3

Final call

VUS

PVS1 very strong PM2 supporting

Variant details

Gene

MSH2

Transcript

NM_000251.3

Protein

NP_000242.1:p.(Thr668TrpfsTer7)

gnomAD AF

ClinVar

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

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.

2

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

3

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.

4

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).

Final determination: No criteria-combination rule matched the adjudicated criteria in the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for MSH2 Version 2.0 v2.0 framework, so the variant remains a Variant of Uncertain Significance pending human review.

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
PVS1	Met	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.	cspec pvs1_gene_context gnomad_v2 gnomad_v4
PS1	N/A	PS1 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.
PS2	Not met	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.
PS3	Not met	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.	vcep_functional_assay_svi_documentation_mmr oncokb
PS4	N/A	The InSiGHT VCEP does not utilize PS4 for MMR variant classification; tumor IHC data is addressed through PP4 instead.	cspec
PS5	Not met	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.
PM1	N/A	The 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.'	cspec
PM2	Met	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.	gnomad_v2 gnomad_v4 gnomad_canada
PM4	N/A	The 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.	cspec
PM5	N/A	PM5 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.
PM6	N/A	The InSiGHT VCEP marks PM6 as not applicable; presumed de novo without confirmed parentage is not used for MMR variant classification under this framework.	cspec
PP1	Not met	No co-segregation data available. The case materials contain no pedigree information, and no published co-segregation analyses for this variant were identified.
PP2	N/A	The 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.	cspec
PP3	N/A	PP3 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).	spliceai vcep_hci_priors_msh2
PP4	Not met	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.
PP5	Not met	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.	clinvar
BA1	Not met	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%).	gnomad_v2 gnomad_v4 gnomad_canada
BS1	Not met	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%).	gnomad_v2 gnomad_v4
BS2	Not met	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.
BS3	Not met	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.	vcep_functional_assay_svi_documentation_mmr
BS4	Not met	No co-segregation data showing lack of segregation with disease. The case materials contain no pedigree information.
BP1	N/A	The 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.	cspec
BP2	N/A	The InSiGHT VCEP replaces BP2 with BS2 for MMR variant classification. BP2 is not used under this framework.	cspec
BP3	N/A	The 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.	cspec
BP4	N/A	BP4 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.	vcep_hci_priors_msh2 spliceai
BP5	Not met	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.
BP6	Not met	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.	clinvar
BP7	N/A	BP7 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.	cspec

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