LYFE Sciences · Project HERA
Variant Interpretation · Classification Report
Generated: 2026-07-13
Case ID: NM_000251.3_c.1132del_20260713_174603
Framework: ACMG/AMP 2015
Variant classification summary

NM_000251.3:c.1132del

MSH2  · NP_000242.1:p.(Glu378LysfsTer34)  · NM_000251.3
GRCh37: chr2:47656935 AG>A  ·  GRCh38: chr2:47429796 AG>A
Gene: MSH2 Transcript: NM_000251.3
Final call
VUS
PVS1 very strong PM2 supporting
All criteria require review: For research and educational purposes only.
Variant details
Gene
MSH2
Transcript
NM_000251.3
Protein
NP_000242.1:p.(Glu378LysfsTer34)
gnomAD AF
ClinVar
OncoKB
Likely Oncogenic
Classification rationale
Interpretation summary
Generated evidence synthesis
1
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.
2
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.
Final determination: No criteria-combination rule matched the adjudicated criteria in the Richards et.al., 2015 - Combining rules v2.0.0 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.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.
cspec
PS1 N/A PS1 under the InSiGHT VCEP applies only to missense substitutions encoding the same amino acid change with a different nucleotide change, or same non-canonical splice nucleotide variants. NM_000251.3:c.1132del is a frameshift deletion, not a missense substitution or splice variant.
PS2 Not met VCEP PS2 requires de novo points based on confirmed parental testing. No de novo observation data are available for NM_000251.3:c.1132del in any source reviewed.
PS3 N/A The InSiGHT VCEP functional assay documentation specifies calibrated assays applicable to missense, splice site, and synonymous variants only. NM_000251.3:c.1132del is a frameshift deletion for which no variant-specific functional data were identified in the literature or in the VCEP functional assay spreadsheet. The five papers retrieved (PMID:10946232, PMID:11257106, PMID:15528792, PMID:23391514, PMID:24362816) discuss MMR gene function at the gene level; none mention this specific variant, and none provide functional data for c.1132del.
PS4 N/A PS4 is marked Not Applicable in the InSiGHT MSH2 VCEP v2.0.0 criteria.
cspec
PS5 N/A PS5 is not included in the InSiGHT MSH2 VCEP v2.0.0 criteria; the VCEP marks this criterion as Not Applicable.
cspec
PM1 N/A PM1 is marked Not Applicable in the InSiGHT MSH2 VCEP v2.0.0 criteria. Domain-level assessment is not used under this VCEP framework for MSH2.
cspec
PM2 Met 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.
gnomad_canada gnomad_v4 clinvar
PM4 N/A PM4 is marked Not Applicable in the InSiGHT MSH2 VCEP v2.0.0 criteria.
cspec
PM5 N/A The InSiGHT VCEP PM5 rule applies only to missense changes at an amino acid residue where a different missense change has been classified as Pathogenic/Likely Pathogenic. NM_000251.3:c.1132del is a frameshift deletion, not a missense variant, and the PM5 candidate analysis confirmed no eligible residue-level comparators.
pm5_candidates
PM6 N/A PM6 is marked Not Applicable in the InSiGHT MSH2 VCEP v2.0.0 criteria. De novo assessment is handled by PS2.
cspec
PP1 Not met VCEP PP1 requires segregation analysis with Bayes Likelihood Ratio thresholds. No co-segregation data are available for NM_000251.3:c.1132del in any source reviewed.
PP2 N/A PP2 is marked Not Applicable in the InSiGHT MSH2 VCEP v2.0.0 criteria.
cspec
PP3 N/A The InSiGHT VCEP PP3 rule applies to missense variants (HCI prior probability thresholds) or non-canonical splice variants (SpliceAI delta score ≥ 0.2). NM_000251.3:c.1132del is a frameshift deletion. HCI prior is not applicable (not a substitution), and SpliceAI max delta score is 0.09 (<0.2).
spliceai vcep_hci_priors_msh2
PP4 Not met VCEP PP4 requires MSI-H CRC/endometrial tumors or loss of MMR protein expression consistent with the variant location. No tumor MSI/IHC data are available for patients carrying NM_000251.3:c.1132del in any source reviewed.
PP5 N/A PP5 is not included in the InSiGHT MSH2 VCEP v2.0.0 criteria and is marked Not Applicable.
cspec
BA1 Not met VCEP BA1 requires gnomAD v4 Grpmax filtering allele frequency ≥ 0.001. No population frequency data at or above this threshold have been observed for NM_000251.3:c.1132del. The variant is absent from gnomAD-Canada and absent from ClinVar.
gnomad_canada
BS1 Not met VCEP BS1 requires gnomAD v4 Grpmax filtering allele frequency ≥ 0.0001 and < 0.001. No population frequency data meeting this threshold have been observed for NM_000251.3:c.1132del.
gnomad_canada
BS2 Not met VCEP BS2 requires co-occurrence in trans with a known pathogenic MSH2 variant in a patient with CRC after age 45 without CMMRD features. No co-occurrence data are available for NM_000251.3:c.1132del.
BS3 N/A The InSiGHT VCEP functional assay documentation (calibrated assays and flowchart) applies to missense, splice site, and synonymous variants. NM_000251.3:c.1132del is a frameshift deletion for which these calibrated assays are not designed. No variant-specific functional data demonstrating normal protein function were identified.
BS4 Not met VCEP BS4 requires lack of co-segregation with disease in pedigrees with specified Bayes Likelihood Ratios. No co-segregation data (for or against) are available for NM_000251.3:c.1132del.
BP1 N/A BP1 is marked Not Applicable in the InSiGHT MSH2 VCEP v2.0.0 criteria.
cspec
BP2 N/A BP2 is marked Not Applicable in the InSiGHT MSH2 VCEP v2.0.0 criteria.
cspec
BP3 N/A BP3 is marked Not Applicable in the InSiGHT MSH2 VCEP v2.0.0 criteria.
cspec
BP4 N/A The InSiGHT VCEP BP4 rule applies to missense variants (HCI prior <0.11) or intronic/synonymous variants (SpliceAI delta ≤ 0.1). NM_000251.3:c.1132del is a frameshift deletion, not a missense, intronic, or synonymous variant.
vcep_hci_priors_msh2 spliceai
BP5 Not met VCEP BP5 requires evidence of MSS tumors, intact MMR protein expression inconsistent with the gene, or BRAF V600E/MLH1 methylation findings. No tumor phenotype data are available for NM_000251.3:c.1132del.
BP6 N/A BP6 is marked Not Applicable in the InSiGHT MSH2 VCEP v2.0.0 criteria.
cspec
BP7 N/A The InSiGHT VCEP BP7 rule applies to synonymous (silent) or intronic variants at or beyond -21/+7 splice positions. NM_000251.3:c.1132del is a coding frameshift deletion and does not meet the variant type requirement for BP7.
cspec
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