Variant classification summary

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

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): Deep intronic duplication at positions +32 to +35 of intron 9, well beyond the +7 boundary at which this benign criterion applies to intronic variants.

2

No pathogenic or benign combination rule is satisfied: the single supporting benign criterion (BP7) is below the two supporting criteria required for a benign combination, so the variant is classified as a Variant of Uncertain Significance (VUS).

Final determination: Under the ClinGen InSiGHT MSH6 VCEP v2.0 combination rules no Pathogenic, Likely Pathogenic, Benign, or Likely Benign rule matched the adjudicated criteria (only BP7 supporting met; no PVS1/PS/PM met; BA1 not met; zero Benign.Strong and only one Benign.Supporting criterion met), so the variant defaults to 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	PVS1 (loss-of-function) is not met. This variant is a 4-base-pair duplication located deep within intron 9 (32 bases past the exon 9 donor splice site), so it is not a nonsense or frameshift change, does not disrupt the canonical splice sites, and is not a large or exon-level alteration. It is predicted to leave the protein unchanged (p.?) and in silico splice prediction (SpliceAI, maximum delta score 0.12) indicates no significant splice impact, with no RNA-based assay evidence available; the MSH6 expert panel rules require mRNA confirmation for non-canonical splice variants.	cspec spliceai pvs1_variant_assessment pvs1_gene_context PMID:25741868
PS1	N/A	Not applicable. This criterion compares a variant's protein or splice-site change with a previously established pathogenic variant, but this duplication produces no amino acid change and does not alter a splice nucleotide, so there is nothing to compare.	cspec
PS2	Not assessed	Not assessed: no proband or family information was available. Scoring this criterion requires parental testing results and tumor data to establish a de novo origin, and none were present in the available evidence.
PS3	Not assessed	Not assessed: no functional evidence was available. This criterion requires calibrated laboratory assays or mRNA expression studies demonstrating defective DNA mismatch repair, and no such data existed for this variant.	cspec
PS4	N/A	Not applicable. The MSH6 expert panel specification does not use case-control enrichment for this gene (tumor-phenotype rules PP4/BP5 replace it), and no case-control study has reported this variant.	cspec
PM1	N/A	Not applicable. The MSH6 expert panel specification declares this criterion unused for MSH6, and the variant is intronic with no missense change that could fall within a functional domain or hotspot.	cspec
PM2	Not met	Not met. This criterion requires the variant to be absent or extremely rare in population databases (below about 1 in 50,000 alleles). The variant is observed in gnomAD v4.1 at roughly 0.01% (159 of about 1.6 million alleles), approximately five times above the threshold, so it is too common for PM2.	gnomad_v4 gnomad_v2
PM3	Not assessed	Not assessed: no co-occurrence was observed. This criterion scores the variant appearing alongside a second known pathogenic MSH6 variant in a patient with features of constitutional mismatch repair deficiency, and no such case exists in the ClinVar submissions, population data (zero homozygotes), or available literature.	cspec clinvar gnomad_v2 gnomad_v4
PM4	N/A	Not applicable. The expert panel does not use PM4 for MSH6, and this intronic duplication has no predicted protein-length change to evaluate.	cspec PMID:25741868
PM5	N/A	Not applicable. This criterion applies only to a missense change at an amino acid position where a different missense change is pathogenic; this variant is intronic and affects no amino acid residue.	cspec pm5_candidates
PM6	N/A	Not applicable. The MSH6 expert panel specification declares this assumed-de-novo criterion unused, and no parental testing data exists on which it could be based.
PP1	Not assessed	Not assessed: no family data was available. This criterion scores how strongly the variant segregates with disease in pedigrees, and no affected relatives, genotyped family members, or segregation information were present in the evidence.
PP2	N/A	Not applicable. The expert panel does not use PP2 for MSH6, and the variant is not a missense change.	cspec
PP3	Not met	Not met. In silico evidence of pathogenicity is insufficient: the expert panel's splice rule requires a SpliceAI delta score of at least 0.2, and the observed maximum is 0.12; missense predictors do not apply to an intronic duplication.	spliceai cspec
PP4	Not assessed	Not assessed: no tumor phenotype data was available. This criterion scores Lynch-syndrome-consistent tumors (MSI-high, or loss of MMR protein expression), and none of the available ClinVar submissions or literature report tumor features for carriers of this variant.	cspec clinvar PMID:10537275
PP5	N/A	Not applicable. This criterion requires an expert-panel pathogenic classification in ClinVar; all five ClinVar submissions for this variant come from clinical laboratories, with no expert-panel classification among them.	cspec clinvar
BA1	Not met	Not met. Stand-alone benign evidence requires the variant to be common (at least 0.22% of alleles in gnomAD v4); the observed frequency of about 0.02% is roughly ten-fold below that threshold.	gnomad_v4 gnomad_v2
BS1	Not met	Not met, though it is a borderline case flagged for review. The benign-strong frequency range is 0.022-0.22% by the panel's metric, and the observed grpmax filtering allele frequency (about 0.0203%) falls just below the lower bound; raw frequencies in several subpopulations (up to about 0.037%) do exceed the threshold.	gnomad_v4 gnomad_v2
BS2	Not assessed	Not assessed: no qualifying case was available. This criterion requires a documented patient carrying this variant in trans with a known pathogenic MSH6 variant, and no such case-level evidence exists in the available data.
BS3	Not assessed	Not assessed: no functional evidence was available. This criterion requires laboratory assays showing the variant has no effect (for example, no mRNA splicing aberration under nonsense-mediated decay inhibition), and only an in silico SpliceAI prediction (delta 0.12) was available, which does not meet the requirement for lab-based RNA evidence.	cspec
BS4	Not assessed	Not assessed: no family data was available. This criterion scores family members who carry the disease but not the variant (non-segregation), and no such pedigree information existed.
BP1	N/A	Not applicable. The expert panel does not use BP1 for MSH6 because loss of MSH6 function is an established disease mechanism, and this variant is not a missense change.	cspec
BP2	N/A	Not applicable. The MSH6 expert panel substitutes BS2 for this criterion, and no observation of the variant in cis or in trans with a pathogenic MSH6 variant exists in the available evidence.	cspec clinvar
BP3	N/A	Not applicable. The expert panel does not use BP3 for MSH6, and the rule targets in-frame coding insertions/deletions in repeat regions, whereas this is an intronic duplication with no protein consequence (the intronic TAAC repeat context was noted but does not make the rule applicable).	cspec clinvar PMID:25741868
BP4	Not met	Not met, by a narrow margin. This benign criterion requires a SpliceAI delta score of 0.1 or less for intronic variants; the observed maximum is 0.12, slightly above threshold. Because the exceedance is marginal, confirmation with the panel's masked-score option was recommended.	spliceai cspec
BP5	Not assessed	Not assessed: no tumor phenotype data was available. This criterion scores tumor features that argue against the gene (such as microsatellite-stable tumors or loss of MMR proteins inconsistent with MSH6), and none were reported for carriers of this variant.	cspec clinvar PMID:10537275
BP6	N/A	Not applicable. This criterion requires an expert-panel benign classification in ClinVar; the variant's 'Benign/Likely benign' label comes solely from five clinical laboratory submissions, with no expert-panel classification.	cspec clinvar
BP7	Met	Met (Supporting). This variant lies in intron 9 at positions +32 to +35, well beyond the +7 boundary at which the expert panel's BP7 rule applies to intronic variants. The rule is purely positional and does not require a splice prediction, so the borderline SpliceAI score does not negate it.	cspec

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