LYFE Sciences · Project HERA
Variant Interpretation · Classification Report
Generated: 2026-08-13
Case ID: NM_000251.3_c.1255C_T_20260813_131731
Framework: ACMG/AMP 2015
Variant classification summary

NM_000251.3:c.1255C>T

MSH2  · NP_000242.1:p.(Gln419Ter)  · NM_000251.3
GRCh37: chr2:47657059 C>T  ·  GRCh38: chr2:47429920 C>T
Gene: MSH2 Transcript: NM_000251.3
Final call
Pathogenic
PVS1 very strong PM2 supporting PP3 supporting PP5 supporting
All criteria require review: For research and educational purposes only.
Variant details
Gene
MSH2
Transcript
NM_000251.3
Protein
NP_000242.1:p.(Gln419Ter)
gnomAD AF
ClinVar
Pathogenic
OncoKB
Likely Oncogenic
Classification rationale
Interpretation summary
Generated evidence synthesis
1
PVS1 (Very Strong): nonsense p.Gln419Ter creates a premature termination codon within the VCEP's <= codon 891 window, predicted to trigger nonsense-mediated decay.
2
PM2 (Supporting): absent from gnomAD v4.1, below the <0.00002 population-frequency threshold.
3
PP3 (Supporting): SpliceAI max delta 0.36 exceeds the >=0.2 predicted-splice-defect threshold (flagged for human review as redundant with PVS1).
4
PP5 (Supporting): this exact variant is classified Pathogenic by the InSiGHT expert panel in ClinVar (3-star).
5
Overall: Pathogenic per InSiGHT MSH2 VCEP combination Rule4 (1 Very Strong + at least 2 Supporting).
Final determination: Under the ClinGen InSiGHT MSH2 VCEP v2.0 criteria-combination framework, Rule4 (exactly 1 Very Strong pathogenic criterion plus at least 2 Supporting pathogenic criteria) is satisfied by PVS1 very strong + PM2/PP3/PP5 supporting, 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 Met, Very Strong: nonsense p.Gln419Ter creates a premature termination codon at codon 419, within the VCEP's <= codon 891 window and predicted to trigger nonsense-mediated decay.
cspec pvs1_gene_context pvs1_variant_assessment PMID:24278394
PS1 N/A Not applicable: PS1 covers missense substitutions or splice-nucleotide changes, and this is a nonsense change with no alternate-nucleotide comparator.
cspec pm5_candidates clinvar spliceai
PS2 Not assessed Not assessed: no de novo occurrence data exist; no parental testing or de novo assertion is reported for c.1255C>T.
PMID:24278394 cspec clinvar
PS3 Not assessed Not assessed: no calibrated functional assay result exists for c.1255C>T; tumor MSI/IHC evidence belongs to PP4, not PS3.
cspec vcep_functional_assay_svi_documentation_mmr vcep_functional_assay_flowchart PMID:24278394 PMID:24362816
PS4 N/A Not applicable: the InSiGHT MSH2 VCEP uses tumor IHC evidence under PP4 instead of PS4 proband counting.
cspec
PM1 N/A Not applicable: the InSiGHT MSH2 VCEP recognizes no mutational hotspots for MSH2, and the variant is nonsense rather than missense.
cspec vcep_mmr_functional_domains
PM2 Met Met, Supporting: c.1255C>T is absent from gnomAD v4.1 (AF=0), below the 0.00002 (<1 in 50,000 alleles) threshold.
gnomad_v4 gnomad_v2 gnomad_canada cspec
PM3 Not met Not met: zero PM3 points, below the 0.5-point supporting minimum; no in-trans second pathogenic MSH2 variant or biallelic observation exists.
cspec PMID:24278394 clinvar PMID:24362816 PMID:15849733
PM4 N/A Not applicable: declared not applicable by the InSiGHT MSH2 VCEP, and a nonsense substitution causes truncation, not an in-frame length change.
cspec
PM5 N/A Not applicable: PM5 applies only to missense changes, and p.Gln419Ter is a nonsense substitution with no different missense change at codon 419.
cspec pm5_candidates
PM6 N/A Not applicable: the InSiGHT MSH2 VCEP captures unconfirmed de novo evidence within the PS2 point system rather than as PM6.
cspec
PP1 Not assessed Not assessed: no co-segregation data exist; the only report describes a single proband with no meioses or segregation analysis.
PMID:24278394 cspec
PP2 N/A Not applicable: the InSiGHT MSH2 VCEP declares PP2 not applicable, and this variant is nonsense, not missense.
cspec
PP3 Met Met, Supporting: SpliceAI max delta 0.36 exceeds the >=0.2 threshold (predicted donor gain at intron 7 +6) per the VCEP PP3 rule. Flagged for human review: this SpliceAI-based support is mechanistically redundant with PVS1 for a nonsense variant.
spliceai cspec vcep_hci_priors_msh2 bayesdel
PP4 Not assessed Not assessed: no carrier-level tumor phenotype data (MSI or MMR IHC) were available for c.1255C>T.
cspec
PP5 Met Met, Supporting: the InSiGHT expert panel classified this exact variant as Pathogenic in ClinVar (3-star).
clinvar
BA1 Not met Not met: allele frequency is 0 (absent from gnomAD v4.1), far below the >=0.001 (0.1%) BA1 threshold.
gnomad_v4 cspec
BS1 Not met Not met: allele frequency is 0 (absent from gnomAD v4.1), below the 0.0001-0.001 BS1 range.
gnomad_v4 cspec
BS2 Not assessed Not assessed: no in-trans co-occurrence or phase-confirmation data exist for any carrier of c.1255C>T.
cspec
BS3 Not assessed Not assessed: no assay demonstrates proficient function for c.1255C>T, and the mRNA-aberration clause does not apply to nonsense variants.
cspec vcep_functional_assay_svi_documentation_mmr vcep_functional_assay_flowchart PMID:24278394 PMID:24362816
BS4 Not assessed Not assessed: no non-segregation data exist; no affected non-carriers or unaffected carriers are reported for any pedigree.
PMID:24278394 cspec
BP1 N/A Not applicable: the InSiGHT MSH2 VCEP declares BP1 not applicable, as missense is an established MSH2 mechanism.
cspec
BP2 N/A Not applicable: the InSiGHT MSH2 VCEP replaces BP2 with its BS2 rule ('BS2 is used instead').
cspec
BP3 N/A Not applicable: the InSiGHT MSH2 VCEP declares BP3 not applicable, and a nonsense substitution is not an in-frame repeat-region indel.
cspec
BP4 N/A Not applicable: BP4's no-impact clauses target missense, intronic, or synonymous variants; c.1255C>T is exonic nonsense with SpliceAI delta 0.36.
cspec vcep_hci_priors_msh2 spliceai bayesdel
BP5 Not assessed Not assessed: no tumor evidence of an alternative molecular basis (MSS, intact MMR IHC, BRAF V600E, or MLH1 methylation) was available.
cspec
BP6 Not met Not met: the only ClinVar expert-panel classification for this exact variant is Pathogenic (InSiGHT), the opposite direction BP6 requires.
cspec clinvar
BP7 N/A Not applicable: BP7 covers synonymous or intronic variants at or beyond -21/+7, and c.1255C>T is an exonic nonsense change.
cspec
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