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's +7 boundary.

2

Overall: VUS — a single supporting benign criterion reaches neither the Likely Benign (two benign criteria) nor Benign threshold, with zero pathogenic evidence.

Final determination: Under the ClinGen InSiGHT MSH6 VCEP v2.0 criteria-combination framework (Richards et al. 2015 combining rules), the adjudicated criteria - BP7 supporting alone - match no Pathogenic rule (Rules 1-8), no Likely Pathogenic rule (Rules 10-15, 20), no Benign rule (BA1 stand-alone Rule17 or >=2 Strong benign Rule16), and no Likely Benign rule (1 Strong + 1 Supporting benign Rule18 or >=2 Supporting benign Rule19), and no conflicting-evidence rule fires because no benign/pathogenic Strong or Stand-Alone criterion is present; the variant is therefore 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: the 4-bp duplication lies deep in intron 9 (+32 to +35), outside the canonical splice consensus, with no predicted protein-level consequence.	cspec pvs1_variant_assessment pvs1_gene_context spliceai clinvar PMID:25741868
PS1	N/A	Not applicable: this intronic duplication encodes no amino acid change and sits +32 to +35, not at a splice nucleotide, so the PS1 rules cannot apply.	cspec spliceai clinvar
PS2	Not assessed	Not assessed: no de novo occurrence or parental testing data was available for this variant.	cspec
PS3	Not assessed	Not assessed: no functional assay, mRNA splicing, or allelic-expression data was available for this variant.	cspec vcep_functional_assay_svi_documentation_mmr vcep_functional_assay_flowchart spliceai clinvar PMID:10537275
PS4	N/A	Not applicable: the VCEP specification does not use PS4, and no case-control study exists for this variant.	cspec
PM1	N/A	Not applicable: the VCEP recognizes no mutational hotspots in MSH6, and the variant is intronic, not missense.	cspec
PM2	Not met	Not met: gnomAD v4 allele frequency of 9.96e-05 is ~5-fold above the <0.00002 extreme-rarity ceiling.	gnomad_v4 gnomad_v2 cspec
PM3	Not assessed	Not assessed: no second MSH6 variant or phase data existed to test trans co-occurrence.	cspec clinvar gnomad_v4
PM4	N/A	Not applicable: this intronic duplication has no protein-level consequence and cannot cause an in-frame protein length change.	cspec PMID:25741868
PM5	N/A	Not applicable: PM5 requires a missense change at a pathogenic same-residue position, and this variant has no amino acid consequence.	pm5_candidates cspec clinvar
PM6	N/A	Not applicable: the VCEP handles de novo evidence exclusively through PS2.	cspec
PP1	Not assessed	Not assessed: no pedigree or co-segregation data was available for this variant.	cspec
PP2	N/A	Not applicable: the VCEP does not use PP2, and this intronic variant is not missense.	cspec
PP3	Not met	Not met: SpliceAI max delta 0.12 is below the >=0.2 splice-defect threshold.	spliceai cspec
PP4	Not assessed	Not assessed: no MSI, immunohistochemistry, or tumor genome data was available for carriers.	cspec
PP5	N/A	Not applicable: ClinVar has no expert-panel classification of this variant, which PP5 requires.	cspec clinvar
BA1	Not met	Not met: gnomAD v4 Grpmax FAF 0.00020269 is ~10.8-fold below the 0.0022 BA1 threshold.	gnomad_v4 cspec
BS1	Not met	Not met: joint Grpmax FAF 0.00020269 falls just below the 0.00022 BS1 lower bound. Flagged for review: exome-only FAF 0.00030753 exceeds the bound, so the call depends on the metric applied.	gnomad_v4 gnomad_v2 cspec
BS2	Not assessed	Not assessed: no trans co-occurrence with a pathogenic MSH6 variant or clinical phenotype data was available.	cspec vcep_table_for_cmmrd_diagnosis
BS3	Not assessed	Not assessed: no mRNA aberration, functional, or allelic-expression assay data was available.	cspec vcep_functional_assay_svi_documentation_mmr vcep_functional_assay_flowchart spliceai clinvar PMID:10537275
BS4	Not assessed	Not assessed: no non-segregation or meiosis data was available to test against segregation.	cspec
BP1	N/A	Not applicable: the VCEP does not use BP1, and missense changes do cause MSH6 disease.	cspec
BP2	N/A	Not applicable: the VCEP directs that BS2 is used instead of BP2.	cspec
BP3	N/A	Not applicable: this intronic duplication has no in-frame protein consequence, which BP3 requires.	cspec PMID:25741868
BP4	Not met	Not met: SpliceAI max delta 0.12 exceeds the <=0.1 BP4 threshold.	spliceai cspec
BP5	Not assessed	Not assessed: no MSS/IHC, BRAF V600E, or MLH1 methylation tumor data was available.	cspec
BP6	N/A	Not applicable: only non-expert laboratory submissions exist in ClinVar, and BP6 requires an expert-panel classification.	cspec clinvar
BP7	Met	Met (Supporting): the intronic duplication lies at +32 to +35, beyond the +7 boundary the VCEP BP7 rule requires.	cspec

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