Classification rationale

PVS1PM2 VUS

MSH2 c.1132del

PVS1 at Very Strong strength: NM_000251.3:c.1132del is a frameshift deletion in exon 7 of MSH2 introducing a premature termination codon at codon 411 (p.Glu378LysfsTer34), which is ≤ codon 891, meeting the InSiGHT MSH2 VCEP v2.0.0 PVS1 Very Strong rule for null variants.¹ PM2 at Supporting strength: the variant is absent from gnomAD-Canada v1.0 and absent from ClinVar, consistent with extreme rarity in the general population. gnomAD v4.1 frequency data were not retrieved; human review recommended to confirm PM2 status against the VCEP threshold of <0.00002.²

PVS1 + PM2 → VUS

1 cspec ↗

2 gnomad_canada ↗clinvar ↗

Gene diagram · NM_000251.3 · variants mapped to exon structure

MSH2 NM_000251.3

Fetching transcript structure from UCSC…

Applied criteria · 2 applied · 8 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 of MSH2, predicted to introduce a premature termination codon at codon 411 (p.Glu378LysfsTer34). Under the InSiGHT MSH2 VCEP v2.0.0 PVS1 rule, nonsense/frameshift variants introducing a PTC ≤ codon 891 qualify for PVS1 at Very Strong strength. Codon 411 is well below this threshold.

Frameshift deletion in exon 7 introducing PTC at codon 411 (≤891)InSiGHT MSH2 VCEP v2.0.0 PVS1 rule: PTC ≤ codon 891 → PVS1 Very Strong

cspec ↗

✓

PM2 supporting review Pathogenic

The variant is absent from gnomAD-Canada v1.0. Under the InSiGHT VCEP v2.0.0 PM2 rule, absence or extreme rarity (<1 in 50,000 alleles, i.e., <0.00002) in gnomAD v4 qualifies for PM2_Supporting. gnomAD v4.1 data were not available at the time of assessment; however, absence from ClinVar, gnomAD v2.1, and gnomAD-Canada is consistent with extreme rarity in the general population.

Absent from gnomAD-Canada v1.0Absent from ClinVargnomAD v4.1 data unavailable

gnomad_canada ↗gnomad_v4 ↗clinvar ↗

Assessed · not applied

Pathogenic

PS2 VCEP PS2 requires de novo points based on confirmed parental testing.

PP1 VCEP PP1 requires segregation analysis with Bayes Likelihood Ratio thresholds.

PP4 VCEP PP4 requires MSI-H CRC/endometrial tumors or loss of MMR protein expression consistent with the variant location.

Benign

BA1 VCEP BA1 requires gnomAD v4 Grpmax filtering allele frequency ≥ 0.001.

BS1 VCEP BS1 requires gnomAD v4 Grpmax filtering allele frequency ≥ 0.0001 and < 0.001.

BS2 VCEP BS2 requires co-occurrence in trans with a known pathogenic MSH2 variant in a patient with CRC after age 45 without CMMRD features.

BS4 VCEP BS4 requires lack of co-segregation with disease in pedigrees with specified Bayes Likelihood Ratios.

BP5 VCEP BP5 requires evidence of MSS tumors, intact MMR protein expression inconsistent with the gene, or BRAF V600E/MLH1 methylation findings.

N/A · 17 PS1 · PS3 · PS4 · PM1 · PM4 · PM5 · PM6 · PP2 · PP3 · PP5 · BS3 · BP1 · BP2 · BP3 · BP4 · BP6 · BP7

Research & evidence

Population frequency

v4.1

This variant is absent from gnomAD v4.1.

v2.1

This variant is absent from gnomAD v2.1.

🇨🇦 CA

Absent from gnomAD-Canada v1.0.

Allele frequency by ancestry

three datasets · side by side

gnomAD Canada 🇨🇦

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v4 ↗ gnomAD v2 ↗ gnomAD 🇨🇦 ↗

ClinVar

This variant is absent from ClinVar.

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.09).

SpliceAI ↗

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.

OncoKB ↗

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.

COSMIC ↗ Hotspots ↗

Sources & reference links

9Sources

CSpec VCEP

ClinVar

gnomAD v2.1

gnomAD v4.1

gnomAD-Canada

SpliceAI

OncoKB

COSMIC

Cancer hotspots

Triaged references · 5 PMIDs not cited in assessment

10946232 ↗ Structure and function of mismatch repair proteins. ONCOKB

11257106 ↗ Deficient DNA mismatch repair: a common etiologic factor for colon cancer. ONCOKB

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