Variant classification summary

NM_000251.2:c.873_876del

MSH2 · NP_000242.1:p.(Thr292LeufsTer8) · NM_000251.2

GRCh37: chr2:47641484 AACTG>A · GRCh38: chr2:47414345 AACTG>A

Gene: MSH2 Transcript: NM_000251.2

Final call

Pathogenic

PVS1 very strong PM2 supporting PP4 supporting PP5 supporting

Variant details

Gene

MSH2

Transcript

NM_000251.2

Protein

NP_000242.1:p.(Thr292LeufsTer8)

gnomAD AF

ClinVar

Pathogenic

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

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.

2

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.

3

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.

4

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

5

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.

Final determination: Rule4 in the Richards et.al., 2015 - Combining rules v2.0.0 criteria-combination framework is satisfied by the adjudicated criteria, so the variant is classified as Pathogenic.

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	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.	cspec PMID:15217520 PMID:15849733
PS1	N/A	PS1 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.
PS2	Not met	No de novo data are available for this variant. No de novo observations were identified in the literature or ClinVar submissions.
PS3	Not met	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.	vcep_functional_assay_svi_documentation_mmr
PS4	N/A	PS4 is marked as not applicable by the InSiGHT MSH2 VCEP specification.
PS5	N/A	PS5 is not an established ACMG/AMP criterion. Not applicable.
PM1	N/A	PM1 is marked as not applicable by the InSiGHT MSH2 VCEP specification.
PM2	Met	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.	gnomad_v2 gnomad_v4 gnomad_canada
PM4	N/A	PM4 is marked as not applicable by the InSiGHT MSH2 VCEP specification.
PM5	N/A	The 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.
PM6	N/A	PM6 is marked as not applicable by the InSiGHT MSH2 VCEP specification.
PP1	Not met	No co-segregation data are available for this variant. No pedigrees with Bayes likelihood ratio analysis were identified in the literature.
PP2	N/A	PP2 is marked as not applicable by the InSiGHT MSH2 VCEP specification.
PP3	Not met	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.	spliceai
PP4	Met	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.	PMID:15217520 PMID:15849733
PP5	Met	Expert panel International Society for Gastrointestinal Hereditary Tumours (InSiGHT) classified as Pathogenic.	clinvar
BA1	Not met	Variant is absent from gnomAD v4.1. Does not meet BA1 threshold of allele frequency ≥0.1% (≥0.001).	gnomad_v4
BS1	Not met	Variant is absent from gnomAD v4.1. Does not meet VCEP BS1 threshold of grpmax filtering allele frequency ≥0.0001 and <0.001.	gnomad_v4
BS2	Not met	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.
BS3	Not met	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.	vcep_functional_assay_svi_documentation_mmr
BS4	Not met	No co-segregation data are available to evaluate lack of segregation with disease. No pedigrees with Bayes likelihood ratio analysis were identified.
BP1	N/A	BP1 is marked as not applicable by the InSiGHT MSH2 VCEP specification.
BP2	N/A	BP2 is marked as not applicable by the InSiGHT MSH2 VCEP specification.
BP3	N/A	BP3 (in-frame deletions/insertions in repetitive regions without known function) is marked as not applicable by the InSiGHT MSH2 VCEP specification.
BP4	Not met	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.
BP5	Not met	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.	PMID:15217520
BP6	N/A	BP6 is marked as not applicable by the InSiGHT MSH2 VCEP specification.
BP7	Not met	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.

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