NM_000251.3:c.1132del is a frameshift deletion in exon 7 of MSH2 that introduces a premature termination codon at codon 412 (p.Glu378LysfsTer34), satisfying PVS1_VeryStrong per the InSiGHT MMR VCEP (PTC ≤ codon 891).1 The variant is absent from gnomAD v4.1, satisfying PM2_Supporting per InSiGHT VCEP (allele frequency <0.00002).2 No other pathogenic or benign criteria are met. The variant is absent from ClinVar; no tumor pathology, functional assay, segregation, or de novo data are available. The five publications reviewed are gene-level reviews that do not mention NM_000251.3:c.1132del.3 Under the InSiGHT MMR VCEP combining rules, PVS1_VeryStrong requires at least 1 Strong, 2 Moderate, 1 Moderate + 1 Supporting, or 2 Supporting criteria in combination to reach Pathogenic; or 1 Moderate to reach Likely Pathogenic. With only PM2_Supporting in addition to PVS1_VeryStrong, none of these thresholds are met.4 This variant is classified as a Variant of Uncertain Significance (VUS) under the InSiGHT MMR VCEP framework: 1 × PVS1_VeryStrong + 1 × PM2_Supporting does not satisfy any Pathogenic or Likely Pathogenic combining rule.5
MSH2
Final classification
VUS
MSH2 c.1132del · p.Glu378LysfsTer34
MSH2
NM_000251.3:c.1132del is a frameshift deletion in exon 7 of MSH2 that introduces a premature termination codon at codon 412 (p.Glu378LysfsTer34), satisfying PVS1_VeryStrong per the InSiGHT MMR VCEP (PTC ≤ codon 891).
Richards et.al., 2015 - Combining rules v2.0.0 criteria-combination framework was evaluated deterministically with applied criteria: PVS1 very strong, PM2 supporting; no rule matched the adjudicated criteria.
Classification rationale
PVS1PM2
VUS
MSH2 c.1132del
PVS1 + PM2
→
VUS
Gene diagram
· NM_000251.3 · variants mapped to exon structure
MSH2
NM_000251.3
Fetching transcript structure from UCSC…
Applied criteria · 2 applied · 11 assessed
Applied · 2
Strength
Supporting
Moderate
Strong
Very strong
✓
PVS1
very strong
Pathogenic
NM_000251.3:c.1132del is a frameshift deletion in exon 7 that introduces a premature termination codon at codon 412 (p.Glu378LysfsTer34), well below the codon 891 threshold specified by the InSiGHT MMR VCEP for PVS1_VeryStrong in MSH2.
Frameshift deletion at c.1132 introduces PTC at codon 412which is ≤ codon 891 per InSiGHT VCEP PVS1 Appendix.MSH2 loss-of-function is an established disease mechanism for Lynch syndrome.
✓
PM2
supporting
Pathogenic
NM_000251.3:c.1132del is absent from gnomAD v4.1, satisfying the InSiGHT VCEP PM2_Supporting criterion (allele frequency <0.00002, i.e., <1 in 50,000 alleles).
Absent from gnomAD v4.1 (0 alleles).Also absent from gnomAD v2.1 and gnomAD-Canada v1.0.
Assessed · not applied
Pathogenic
PS2
No de novo observations for NM_000251.3:c.1132del were identified in ClinVar, the literature, or any reviewed source.
PS3
The InSiGHT VCEP PS3 calibrated functional assay documentation is limited to missense, splice site, and synonymous variant types; no validated functional assay data exist for frameshift variants such as c.1132del.
PP1
No co-segregation data are available for NM_000251.3:c.1132del in any reviewed source.
PP3
No in silico evidence supports pathogenicity for this frameshift variant.
PP4
No tumor MSI or IHC data are available for NM_000251.3:c.1132del to satisfy the InSiGHT VCEP PP4 criterion (≥1 CRC/endometrial MSI-H tumor with consistent MMR protein loss).
Benign
BA1
NM_000251.3:c.1132del is absent from gnomAD v4.1; allele frequency does not reach the BA1 threshold (≥0.1% Grpmax FAF).
BS1
NM_000251.3:c.1132del is absent from gnomAD v4.1; allele frequency does not reach the InSiGHT VCEP BS1 threshold (≥0.01% and <0.1% Grpmax FAF, excluding founder variants).
BS2
No evidence of co-occurrence in trans with a known pathogenic MSH2 variant was identified in any reviewed source.
BS3
The InSiGHT VCEP BS3 calibrated functional assay documentation is limited to missense, splice site, and synonymous variant types; no functional data demonstrating normal protein function exist for this frameshift variant.
BS4
No segregation data are available to demonstrate lack of co-segregation with disease for NM_000251.3:c.1132del.
BP5
No tumor data are available to demonstrate microsatellite stability, intact MMR protein expression, or an alternative molecular basis (e.g., BRAF V600E, MLH1 methylation) for tumors harboring NM_000251.3:c.1132del.
N/A · 15
PS1 · PS4 · PM1 · PM3 · PM4 · PM5 · PM6 · PP2 · PP5 · BP1 · BP2 · BP3 · BP4 · BP6 · BP7
Research & evidence
Population frequency
gnomAD v4.1
gnomAD v2.1
v4.1
Absent from gnomAD v4.1.
v2.1
Absent from gnomAD v2.1.
🇨🇦 CA
Absent from gnomAD-Canada v1.0.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
gnomAD v2.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
gnomAD Canada 🇨🇦
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.09).
Functional
Likely Oncogenic
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.
COSMIC
Cancer hotspots
Somatic evidence
Not in COSMIC / hotspots
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Hotspots
This variant does not lie in a statistically significant hotspot.
Sources & reference links
9Sources
Triaged references · 5 PMIDs not cited in assessment
15528792 ↗
Mutations associated with HNPCC predisposition -- Update of ICG-HNPCC/INSiGHT mutation database.
ONCOKB
23391514 ↗
Structural, molecular and cellular functions of MSH2 and MSH6 during DNA mismatch repair, damage signaling and other noncanonical activities.
ONCOKB
24362816 ↗
Application of a 5-tiered scheme for standardized classification of 2,360 unique mismatch repair gene variants in the InSiGHT locus-specific database.
ONCOKB