Variant classification summary

NM_000251.3:c.2005+1G>A

MSH2 · NP_000242.1:p.? · NM_000251.3

GRCh37: chr2:47702410 G>A · GRCh38: chr2:47475271 G>A

Gene: MSH2 Transcript: NM_000251.3

Final call

Likely Pathogenic

PVS1 strong PM2 supporting PP4 supporting PP5 supporting

Variant details

Gene

MSH2

Transcript

NM_000251.3

Protein

NP_000242.1:p.?

gnomAD AF

ClinVar

Likely pathogenic

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PVS1 (Strong): canonical +1 splice-donor variant; in-frame exon 12 skipping (SpliceAI delta 1.00) deletes ~82 amino acids encompassing the EXO1-binding and ATP-binding (Walker A) regions, a functionally critical segment.

2

PM2 (Supporting): absent from gnomAD v4.1 (AF = 0), below the <0.00002 allele-frequency threshold.

3

PP4 (Supporting): one MSI-H colorectal tumor in a documented carrier (PMID:16142001), within the VCEP's 5-10-marker panel requirement.

4

PP5 (Supporting): ClinVar 3-star InSiGHT expert-panel classification of Likely pathogenic.

5

Combination: Likely Pathogenic by VCEP Rule 12 (1 Pathogenic Strong + 3 Pathogenic Supporting), with no conflicting benign evidence.

Final determination: Rule12 of the ClinGen InSiGHT MSH2 VCEP v2.0 combination framework (1 Pathogenic.Strong + >=2 Pathogenic.Supporting -> Likely Pathogenic) is satisfied by PVS1 strong together with PM2, PP4, and PP5 supporting, so the variant NM_000251.3(MSH2):c.2005+1G>A is classified as Likely 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 (Strong): canonical +1 splice-donor variant predicted to skip in-frame exon 12 (SpliceAI delta 1.00), deleting a functionally critical ~82-amino-acid region. Not upgraded to Very Strong because no RNA assay confirmed the splice defect.	cspec spliceai
PS1	N/A	Not applicable: PS1 applies only to missense or non-canonical splice variants; this canonical +1 splice-donor variant produces no amino-acid change.	cspec clinvar pvs1_variant_assessment spliceai
PS2	Not assessed	Not assessed: no de novo occurrence or parental testing is reported for this variant in ClinVar or the literature.	cspec clinvar PMID:15849733
PS3	Not assessed	Not assessed: no variant-specific functional assay result exists; the only published report documents an MSI-H tumor, a phenotype observation rather than a functional test.	cspec vcep_functional_assay_svi_documentation_mmr vcep_functional_assay_flowchart PMID:16142001 PMID:15849733 PMID:24362816 PMID:16199547
PS4	N/A	Not applicable: the InSiGHT MSH2 VCEP scores tumor MSI/IHC evidence under PP4 and does not use PS4 proband counting.	cspec
PM1	N/A	Not applicable: the VCEP recognizes no MSH2 mutational hotspots usable for PM1, and this intronic variant has no amino-acid position.	cspec
PM2	Met	Met (Supporting): absent from gnomAD v4.1 (AF = 0), below the <1-in-50,000 (<0.00002) allele-frequency threshold.	gnomad_v4 gnomad_v2 gnomad_canada clinvar cspec
PM3	Not assessed	Not assessed: no second pathogenic MSH2 variant in trans (or of unknown phase) in a CMMRD-consistent patient is reported for this variant.	cspec vcep_table_for_cmmrd_diagnosis
PM4	N/A	Not applicable: the VCEP does not use in-frame protein-length-change evidence, and this splice variant is not an in-frame indel.	cspec
PM5	N/A	Not applicable: PM5 requires a missense change at a residue where a different pathogenic missense exists; this splice variant produces no amino-acid change.	cspec pm5_candidates
PM6	N/A	Not applicable: the VCEP folds assumed-de-novo evidence into its PS2 points system rather than a separate PM6 code.	cspec
PP1	Not assessed	Not assessed: no pedigree or segregation data exist for this variant, so no co-segregation likelihood ratio could be computed.	cspec clinvar PMID:15849733 PMID:24362816
PP2	N/A	Not applicable: the VCEP does not apply PP2 to MSH2, and this splice variant is not a missense change.	cspec
PP3	N/A	Not applicable: PP3 covers non-canonical splice sites only; this canonical +1 variant's splice prediction is scored under PVS1 instead.	cspec spliceai vcep_hci_priors_msh2 bayesdel
PP4	Met	Met (Supporting): one MSI-H colorectal tumor in a documented carrier (PMID:16142001, 6-marker panel) satisfies the VCEP PP4_Supporting rule.	PMID:16142001 cspec
PP5	Met	Met (Supporting): ClinVar 3-star InSiGHT expert panel classifies this variant Likely pathogenic.	clinvar
BA1	Not met	Not met: allele frequency 0 in gnomAD v4, far below the >=0.001 (0.1%) BA1 threshold.	gnomad_v4 gnomad_v2 cspec
BS1	Not met	Not met: absent from gnomAD (AF = 0), below the >=0.0001 (0.01%) lower bound of the BS1 range.	gnomad_v4 gnomad_v2 gnomad_canada cspec
BS2	Not assessed	Not assessed: no proband or family genotype data show in-trans co-occurrence with a known pathogenic MSH2 variant.	cspec vcep_table_for_cmmrd_diagnosis
BS3	Not assessed	Not assessed: no assay demonstrates normal splicing or normal MMR function; insufficient evidence was available.	cspec vcep_functional_assay_svi_documentation_mmr vcep_functional_assay_flowchart PMID:16142001 PMID:15849733 PMID:24362816 PMID:16199547
BS4	Not assessed	Not assessed: no pedigrees show affected non-carriers or unaffected carriers, so non-segregation could not be scored.	cspec clinvar
BP1	N/A	Not applicable: the VCEP does not apply BP1 to MSH2, and this splice variant is not a missense change.	cspec
BP2	N/A	Not applicable: the VCEP replaces BP2 with BS2 for MSH2, and no co-occurrence data exist for this variant.	cspec
BP3	N/A	Not applicable: the VCEP does not use BP3, and this splice variant is not an in-frame indel in a repetitive region.	cspec
BP4	Not met	Not met: SpliceAI max delta 1.00 far exceeds the <=0.1 no-splice-impact threshold.	cspec spliceai vcep_hci_priors_msh2 bayesdel
BP5	Not assessed	Not assessed: no MSS tumors, retained-MMR-IHC results, or BRAF/MLH1 methylation data exist for carriers of this variant.	cspec
BP6	Not met	Not met: the only expert-panel ClinVar classification (InSiGHT, 3 stars) is Likely pathogenic, not benign.	clinvar cspec
BP7	Not met	Not met: position +1 lies inside the canonical splice region, not at or beyond +7, and SpliceAI predicts strong splice impact.	cspec spliceai

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