Variant classification summary

NM_000179.3:c.4002-16_4002-10del

MSH6 · NP_000170.1:p.? · NM_000179.3

GRCh37: chr2:48033890 CTTTTTTT>C · GRCh38: chr2:47806751 CTTTTTTT>C

Gene: MSH6 Transcript: NM_000179.3

Final call

VUS

PM2 supporting BP4 supporting

Variant details

Gene

MSH6

Transcript

NM_000179.3

Protein

NP_000170.1:p.?

gnomAD AF

4.153266613412559e-06 (v4.1)

ClinVar

Uncertain significance

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PM2 (Supporting): absent or extremely rare in gnomAD v4, with Grpmax FAF 5.02e-06 below the <0.00002 threshold.

2

BP4 (Supporting): SpliceAI predicts no splice impact (max delta 0.00), below the <=0.1 threshold for intronic variants.

3

Combined under Rule31 (at least one pathogenic-supporting and one benign-supporting criterion), the final classification is Uncertain Significance due to conflicting evidence.

Final determination: Rule31: >=1 Benign.Supporting + >=1 Pathogenic.Supporting → Uncertain Significance - Conflicting Evidence.

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	N/A	Not applicable: a deep intronic 7-bp deletion outside the canonical splice sites, with SpliceAI max delta 0.00, does not meet any loss-of-function rule branch.	cspec spliceai
PS1	Not met	Not met: a deep intronic deletion with unknown protein consequence cannot match a known pathogenic missense at the same residue.	cspec spliceai
PS2	Not assessed	Not assessed: no de novo observation, parental testing, or qualifying tumor evidence was available.	cspec clinvar
PS3	Not assessed	Not assessed: no variant-specific functional assay or mRNA expression data was available.
PS4	N/A	Not applicable: the MSH6 VCEP specification designates PS4 as not applicable for this gene.	cspec
PM1	N/A	Not applicable: the MSH6 VCEP specification designates PM1 as not applicable for this gene.	cspec
PM2	Met	Met (Supporting): gnomAD v4 Grpmax FAF of 5.02e-06 is below the <0.00002 rarity threshold.	cspec gnomad_v4
PM3	Not assessed	Not assessed: no second MSH6 variant, phase, or family-testing evidence was available.	cspec
PM4	N/A	Not applicable: designated by the MSH6 VCEP, and the intronic deletion has no in-frame protein consequence.	cspec spliceai
PM5	N/A	Not applicable: a deep intronic deletion with unknown protein consequence is not a missense change eligible for same-residue comparison.	pm5_candidates cspec
PM6	N/A	Not applicable: the MSH6 VCEP designates PM6 as not applicable; de novo evidence is evaluated under PS2 instead.	cspec
PP1	Not assessed	Not assessed: no pedigree or cosegregation data was available to quantify a Bayes likelihood ratio.	cspec clinvar
PP2	N/A	Not applicable: designated by the MSH6 VCEP, and the variant is intronic rather than missense.	cspec
PP3	Not met	Not met: SpliceAI max delta 0.00 versus the >=0.2 splice-impact threshold.	spliceai cspec
PP4	Not assessed	Not assessed: no patient or family phenotype, MSI tumor, or MMR protein-expression data was available.	cspec
PP5	N/A	Not applicable: designated by the MSH6 VCEP, and the ClinVar record holds only a single-submitter uncertain assertion.	cspec clinvar
BA1	Not met	Not met: gnomAD v4 Grpmax FAF 5.02e-06 (0.000502%) versus the >=0.0022 (0.22%) BA1 threshold.	cspec gnomad_v4
BS1	Not met	Not met: gnomAD v4 Grpmax FAF 5.02e-06 falls below the required 0.00022-0.0022 range.	cspec gnomad_v4
BS2	Not assessed	Not assessed: no clinical co-occurrence, phase, or age evidence was available.	cspec
BS3	Not assessed	Not assessed: no calibrated wet-lab functional or mRNA assay data was available; computational SpliceAI predictions do not qualify.
BS4	Not assessed	Not assessed: no pedigree or segregation observations were available to demonstrate lack of cosegregation.	cspec clinvar
BP1	N/A	Not applicable: the MSH6 VCEP specification designates BP1 as not applicable for this gene.	cspec
BP2	N/A	Not applicable: the MSH6 VCEP designates BP2 as not applicable; BS2 is used instead.	cspec
BP3	N/A	Not applicable: designated by the MSH6 VCEP, and the variant is intronic rather than an in-frame protein indel.	cspec
BP4	Met	Met (Supporting): SpliceAI max delta 0.00, below the <=0.1 no-splice-impact threshold for intronic variants.	spliceai cspec
BP5	Not assessed	Not assessed: no qualifying tumor observations (MSI, MMR expression, BRAF/MLH1 methylation) were available.	cspec
BP6	N/A	Not applicable: designated by the MSH6 VCEP, with no expert-panel benign classification on record.	cspec clinvar
BP7	Not met	Not met: the intronic deletion at -16 to -10 lies closer to the exon than the required -21 boundary.	cspec

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