Variant classification summary

NM_000179.3:c.4001+32_4001+35dup

MSH6 · NP_000170.1:p.? · NM_000179.3

GRCh37: chr2:48033816 A>ATAAC · GRCh38: chr2:47806677 A>ATAAC

Gene: MSH6 Transcript: NM_000179.3

Final call

VUS

BP7 supporting

Variant details

Gene

MSH6

Transcript

NM_000179.3

Protein

NP_000170.1:p.?

gnomAD AF

9.956155346079716e-05 (v4.1)

ClinVar

Likely benign

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

1

BP7 (Supporting): intronic variant at +32 to +35, beyond the VCEP -21/+7 boundary.

2

Overall: VUS — one Benign Supporting criterion alone matches no combination rule; Likely Benign would require at least two Supporting criteria or a Strong plus a Supporting.

Final determination: Under the ClinGen InSiGHT MSH6 VCEP v2.0 criteria-combination framework, the single applied Benign Supporting criterion (BP7) matches no combination rule (Likely Benign requires >=2 Benign.Supporting or 1 Benign.Strong + 1 Benign.Supporting; Benign requires >=2 Benign.Strong or BA1; all Pathogenic/Likely Pathogenic rules require at least one Very Strong/Strong/Moderate pathogenic criterion), so the variant is classified as Variant of Uncertain Significance.

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 met	Not met: this deep intronic duplication (intron 9, +32 to +35) creates no premature stop codon and matches no VCEP PVS1 tier.	cspec spliceai pvs1_variant_assessment pvs1_gene_context clinvar gnomad_v4
PS1	N/A	Not applicable: an intronic duplication with no protein consequence, so no same-amino-acid or same-splice-nucleotide pathogenic comparison exists.	cspec spliceai clinvar
PS2	Not assessed	Not assessed: no de novo occurrence or parental-testing data were available to score.	clinvar cspec
PS3	Not assessed	Not assessed: no calibrated functional assay, MMR function test, or mRNA expression data were available.	cspec vcep_functional_assay_svi_documentation_mmr vcep_functional_assay_flowchart spliceai PMID:25741868
PS4	N/A	Not applicable: the MSH6 VCEP captures case-control enrichment through the PP4/BP5 tumor-phenotype rules and declares PS4 not applicable.	cspec
PM1	N/A	Not applicable: the MSH6 VCEP recognizes no mutational hotspots, and this intronic variant alters no residue.	cspec
PM2	Not met	Not met: gnomAD v4.1 allele frequency 0.00996% (159/1,597,002 alleles) is about 5-fold above the <0.002% threshold.	gnomad_v4 gnomad_v2 cspec
PM3	Not assessed	Not assessed: no second MSH6 variant, phase testing, or CMMRD-consistent clinical features were available to score co-occurrence.	cspec clinvar PMID:25741868
PM4	N/A	Not applicable: the MSH6 VCEP declares PM4 not applicable, and this intronic duplication changes no protein length.	cspec
PM5	N/A	Not applicable: not a missense change, so no same-residue comparison with a VCEP-classified pathogenic missense exists.	cspec pm5_candidates
PM6	N/A	Not applicable: the MSH6 VCEP captures de novo evidence under PS2 and declares PM6 not applicable.	cspec
PP1	Not assessed	Not assessed: no pedigree or co-segregation data were available to compute a likelihood ratio.	clinvar cspec
PP2	N/A	Not applicable: the MSH6 VCEP declares PP2 not applicable, and the variant is intronic, not missense.	cspec
PP3	Not met	Not met: SpliceAI max delta 0.12 is below the >=0.2 PP3 splice threshold, and the variant is not a missense.	spliceai cspec vcep_hci_priors_msh6
PP4	Not assessed	Not assessed: no MSI status, MMR-immunohistochemistry results, or tumor-phenotype case reports were available.	cspec clinvar PMID:10537275
PP5	N/A	Not applicable: no ClinVar expert-panel classification exists for this variant, so the global PP5 rule cannot trigger.	cspec clinvar
BA1	Not met	Not met: gnomAD v4.1 grpmax FAF 0.0203% is an order of magnitude below the 0.22% BA1 threshold.	gnomad_v4 gnomad_v2 cspec
BS1	Not met	Not met: joint-callset grpmax FAF 0.0203% sits just below the 0.022% BS1 floor. Flagged for human review: the exome-only grpmax FAF (0.0308%) would meet BS1, so the intended gnomAD metric must be confirmed.	gnomad_v4 gnomad_v2 cspec
BS2	Not assessed	Not assessed: no phase-confirmed trans co-occurrence with a pathogenic MSH6 variant in a compatible patient was available.	cspec
BS3	Not assessed	Not assessed: no mRNA/cDNA assay or calibrated functional results were available for this intronic variant.	cspec vcep_functional_assay_svi_documentation_mmr vcep_functional_assay_flowchart spliceai PMID:25741868
BS4	Not assessed	Not assessed: no pedigree-based non-segregation observations were available to compute a likelihood ratio.	clinvar cspec
BP1	N/A	Not applicable: missense variants are a recognized MSH6 disease mechanism, and the VCEP declares BP1 not applicable.	cspec
BP2	N/A	Not applicable: the MSH6 VCEP declares BP2 not applicable, with trans-phase evidence captured instead by BS2.	cspec PMID:25741868
BP3	N/A	Not applicable: the MSH6 VCEP declares BP3 not applicable, and this is an intronic, not in-frame coding, duplication.	cspec
BP4	Not met	Not met: SpliceAI max delta 0.12 exceeds the <=0.1 BP4 cutoff.	spliceai cspec vcep_hci_priors_msh6
BP5	Not assessed	Not assessed: no MSS, MMR-immunohistochemistry, or BRAF V600E/MLH1-methylation tumor data were available.	cspec clinvar PMID:10537275
BP6	N/A	Not applicable: no ClinVar expert-panel classification exists for this variant, so the global BP6 rule cannot trigger.	cspec clinvar
BP7	Met	Met (Supporting): intronic variant at +32 to +35, beyond the VCEP -21/+7 boundary.	cspec

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