LYFE Sciences · Project HERA
Variant Interpretation · Classification Report
Generated: 2026-10-29
Case ID: NM_000251.3_c.942_3A_T_20261029_141517
Framework: ACMG/AMP 2015
Variant classification summary

NM_000251.3:c.942+3A>T

MSH2  · NP_000242.1:p.?  · NM_000251.3
GRCh37: chr2:47641560 A>T  ·  GRCh38: chr2:47414421 A>T
Gene: MSH2 Transcript: NM_000251.3
Final call
VUS
PS3 moderate PP3 supporting PP4 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.?
gnomAD AF
0.002676567086858919 (v4.1)
ClinVar
Pathogenic
OncoKB
Classification rationale
Interpretation summary
Generated evidence synthesis
1
PS3 Moderate: patient-derived RNA shows MSH2 exon 5 skipping and an in-frame 50-amino-acid deletion.
2
PP3 Supporting: SpliceAI maximum delta score 0.486 exceeds the VCEP splice-impact threshold of 0.2.
3
PP4 Supporting: variant-specific colorectal tumors were MSI-high with MSH2/MSH6 loss.
4
PP5 Supporting: an expert panel classified the variant as Pathogenic.
Final determination: Under the MSH2 VCEP framework, one Moderate criterion requires at least four Supporting criteria for Likely Pathogenicity (Rule15); PS3 Moderate with only three Supporting criteria therefore remains VUS.
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 Not assessed Not assessed: RNA studies show exon 5 skipping and a 50-amino-acid in-frame deletion, but do not establish absent full-length transcript or disrupted protein function.
cspec vcep_pvs1_decisiontree_mmr PMID:10978353 PMID:16395668 PMID:19267393 PMID:19419416
PS1 Not assessed Not assessed: SpliceAI max delta is 0.486, but no different Pathogenic or Likely Pathogenic comparator at c.942+3 was identified for the VCEP same-nucleotide route.
cspec spliceai clinvar PMID:10978353 PMID:16395668 PMID:19267393 PMID:19419416
PS2 Not assessed Not assessed: recurrent de novo origin is reported, but no qualifying proband has documented parentage confirmation and the VCEP-required tumor evidence for point assignment.
cspec PMID:10978353
PS3 Met Met at Moderate: patient-derived RNA studies show c.942+3A>T causes MSH2 exon 5 skipping and an in-frame 50-amino-acid deletion, meeting the VCEP splice-assay defect pathway.
cspec vcep_functional_assay_svi_documentation_mmr vcep_functional_assay_flowchart PMID:10978353 PMID:16395668 PMID:19267393 PMID:19419416
PS4 N/A Not applicable: the MSH2 VCEP explicitly excludes PS4 proband-counting classification when tumor IHC data are available.
cspec
PM1 N/A Not applicable: the MSH2 VCEP explicitly marks PM1 “Not Applicable,” and the governing domain file has no entry for c.942+3A>T or p.? .
cspec vcep_mmr_functional_domains
PM2 Not met Not met: gnomAD v4.1 AF is 0.00267657, exceeding the VCEP PM2 threshold of <0.00002 by more than two orders of magnitude.
cspec gnomad_v4
PM3 Not assessed Not assessed: affected proband and family reports lack a documented second pathogenic MSH2 variant with confirmed trans phase needed to assign PM3 points.
cspec PMID:10978353 PMID:12352241 PMID:16203774 PMID:19267393
PM4 N/A Not applicable: the MSH2 VCEP marks PM4 not applicable and does not use protein-length change from an in-frame variant.
cspec
PM5 N/A Not applicable: PM5 requires a missense change at an amino-acid residue, whereas this variant is intronic with protein consequence p.? .
cspec pm5_candidates
PM6 N/A Not applicable: the MSH2 VCEP specification explicitly marks PM6 as not applicable.
cspec
PP1 Not assessed Not assessed: segregation is reported across 12 and 10 families, but no combined Bayes Likelihood Ratio is available for comparison with the VCEP thresholds.
cspec PMID:12352241 PMID:10978353
PP2 N/A Not applicable: the governing MSH2 VCEP explicitly marks PP2 “Not Applicable.”
cspec
PP3 Met Met: SpliceAI maximum delta score 0.486 meets the VCEP PP3 Supporting threshold of >=0.2 for a non-canonical splice nucleotide.
cspec spliceai vcep_hci_priors_msh2
PP4 Met Met at Supporting: colorectal-cancer tumors were MSI-high with MSH2/MSH6 loss, satisfying the VCEP requirement for one consistent MSI-H tumor.
cspec PMID:19267393 PMID:16203774
PP5 Met Not applicable: the MSH2 VCEP prohibits PP5 use, regardless of pathogenic reports from reputable sources.
cspec clinvar
BA1 Not met Not met: gnomAD v4.1 Grpmax FAF is 0.00234998, but the variant is reported as a founder mutation and therefore is not excluded as founder pathogenic.
cspec gnomad_v4 PMID:16203774
BS1 Not met Not met: gnomAD v4.1 Grpmax FAF is 0.00234998, exceeding the BS1 upper limit of <0.001 and accompanied by founder-mutation evidence.
cspec gnomad_v4 PMID:16203774
BS2 Not assessed Not assessed: no patient-level report documents a known pathogenic MSH2 variant in trans with confirmed phase and the VCEP-required clinical context.
cspec
BS3 Not met Not met: patient-derived RNA studies show exon 5 skipping and deletion, whereas BS3 requires no mRNA aberration or variant-specific proficient function.
cspec vcep_functional_assay_svi_documentation_mmr vcep_functional_assay_flowchart PMID:10978353 PMID:16395668 PMID:19267393 PMID:19419416
BS4 Not assessed Not assessed: no non-segregating pedigree analysis or combined Bayes Likelihood Ratio is available for comparison with the VCEP thresholds.
cspec
BP1 N/A Not applicable: the governing MSH2 VCEP explicitly marks BP1 “Not Applicable.”
cspec
BP2 N/A Not applicable: the MSH2 VCEP specification explicitly designates BP2 as Not Applicable.
cspec
BP3 N/A Not applicable: the MSH2 VCEP marks BP3 not applicable and does not use in-frame repeat-region deletions or insertions without known function.
cspec
BP4 Not met Not met: SpliceAI maximum delta score 0.486 exceeds the VCEP BP4 no-splicing-impact cutoff of <=0.1.
cspec spliceai vcep_hci_priors_msh2
BP5 Not assessed Not assessed: available tumors were MSI-high with MSH2/MSH6 loss, not the VCEP-defined MSS, absent-loss, or BRAF/MLH1-methylation patterns.
cspec PMID:19267393 PMID:16203774
BP6 N/A Not applicable: the MSH2 VCEP prohibits BP6 use, regardless of any benign report from a reputable source.
cspec
BP7 N/A Not applicable: c.942+3A>T is intronic at +3, inside the VCEP BP7 boundary requiring intronic variants at or beyond +7.
cspec
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