Variant classification summary

NM_000179.3:c.3261dup

MSH6 · NP_000170.1:p.(Phe1088LeufsTer5) · NM_000179.3

GRCh37: chr2:48030639 A>AC · GRCh38: chr2:47803500 A>AC

Gene: MSH6 Transcript: NM_000179.3

Final call

VUS

PVS1 very strong PP5 supporting

Variant details

Gene

MSH6

Transcript

NM_000179.3

Protein

NP_000170.1:p.(Phe1088LeufsTer5)

gnomAD AF

5.652026468874725e-05 (v4.1)

ClinVar

Pathogenic

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PVS1 very strong: the frameshift creates a premature stop at approximately codon 1092, below the MSH6 VCEP cutoff of codon 1341.

2

PP5 supporting: an InSiGHT expert-panel pathogenic classification was recorded, but it is insufficient with PVS1 alone to meet a VCEP combination rule.

Final determination: Under the MSH6 VCEP criteria-combination framework, PVS1 very strong plus only one supporting criterion does not satisfy a pathogenic or benign rule, so the variant remains VUS.

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, very strong: the frameshift creates a premature stop at approximately codon 1092, below the MSH6 VCEP cutoff of codon 1341.	cspec vcep_pvs1_decisiontree_mmr pvs1_variant_assessment PMID:18809606
PS1	N/A	Not applicable: c.3261dup is a frameshift, whereas the VCEP PS1 rule requires a same-amino-acid missense substitution or non-canonical splice-nucleotide variant.	cspec pvs1_variant_assessment PMID:18809606
PS2	Not assessed	Not assessed: one affected proband is reported, but parental testing and the de novo points required by the VCEP are not documented.	cspec PMID:18809606
PS3	Not assessed	Not assessed: no variant-specific calibrated functional-assay result or qualifying functional odds were found; the exact variant report only documents MSI in 2 of 5 markers.	cspec vcep_functional_assay_svi_documentation_mmr vcep_functional_assay_flowchart PMID:18809606
PS4	N/A	Not applicable: the MSH6 VCEP explicitly excludes PS4 from MMR classification because tumor IHC evidence is evaluated through PP4 instead.	cspec
PM1	N/A	Not applicable: the VCEP excludes PM1 because no recognized hotspots are used and pathogenic variants are generalized across MMR functional domains.	cspec vcep_mmr_functional_domains
PM2	Not met	Not met: gnomAD v4.1 total AF is 0.0000565203, exceeding the PM2 threshold of <0.00002 (<1 in 50,000 alleles).	cspec gnomad_v4
PM3	Not assessed	Not assessed: the reported proband has c.3261dup, but no second MSH6 pathogenic variant, phase, or CMMRD features are documented for PM3 point assignment.	cspec PMID:18809606
PM4	N/A	Not applicable: the MSH6 VCEP excludes PM4, which concerns in-frame protein-length changes, while this variant is a frameshift.	cspec pvs1_variant_assessment
PM5	N/A	Not applicable: c.3261dup produces a frameshift, while the VCEP PM5 rule requires a missense change and a different classified missense change at the same residue.	cspec pvs1_variant_assessment pm5_candidates
PM6	N/A	Not applicable: the MSH6 VCEP specification explicitly marks PM6 as not applicable.	cspec
PP1	Not assessed	Not assessed: no pedigree-level segregation dataset or combined Bayes Likelihood Ratio is available to compare with the VCEP thresholds.	cspec PMID:18809606
PP2	N/A	Not applicable: the MSH6 VCEP marks PP2 Not applicable, and its stated rule concerns missense variation while this variant is a frameshift.	cspec pvs1_variant_assessment
PP3	N/A	Not applicable: c.3261dup is a frameshift, while PP3 covers missense HCI-prior evidence or non-canonical splice defects with SpliceAI delta score >= 0.2.	cspec
PP4	Not met	Not met: the exact-variant CRC report showed instability in 2 of 5 markers, not the VCEP's MSI-H requirement, with no qualifying MSH6 protein-loss evidence.	cspec vcep_table_for_cmmrd_diagnosis vcep_vcep_pilot_variants_mmr PMID:18809606
PP5	Met	Not applicable: the MSH6 VCEP explicitly prohibits PP5, regardless of pathogenic classifications reported by ClinVar or publications.	cspec clinvar
BA1	Not met	Not met: gnomAD v4.1 Grpmax FAF is 0.00004271 (0.004271%), below the BA1 threshold of ≥0.0022 (0.22%).	cspec gnomad_v4
BS1	Not met	Not met: gnomAD v4.1 Grpmax FAF is 0.00004271, below the BS1 interval beginning at ≥0.00022 (0.022%).	cspec gnomad_v4
BS2	Not assessed	Not assessed: no qualifying in-trans co-occurrence, phase confirmation, cancer-age condition, or CMMRD-status documentation is available.	cspec
BS3	Not assessed	Not assessed: no variant-specific proficient-function result or benign functional odds were found, while the exact report showed MSI in 2 of 5 tumor markers.	cspec vcep_functional_assay_svi_documentation_mmr vcep_functional_assay_flowchart PMID:18809606
BS4	Not assessed	Not assessed: no non-segregation observations or combined Bayes Likelihood Ratio is documented for comparison with the VCEP thresholds.	cspec
BP1	N/A	Not applicable: the MSH6 VCEP marks BP1 Not applicable, and its stated rule concerns missense variants while this variant is a frameshift.	cspec pvs1_variant_assessment
BP2	N/A	Not applicable: the MSH6 VCEP specification explicitly designates BP2 as not applicable.	cspec
BP3	N/A	Not applicable: the MSH6 VCEP marks BP3 as not applicable, and this variant is a truncating frameshift rather than an in-frame repeat-region indel.	cspec pvs1_variant_assessment
BP4	N/A	Not applicable: c.3261dup is a frameshift, whereas BP4 covers missense HCI-prior probability <0.11 or intronic/synonymous SpliceAI delta score <= 0.1.	cspec
BP5	Not assessed	Not assessed: the only exact-variant tumor report showed instability in 2 of 5 markers, not MSS, and lacked the VCEP-required alternate molecular-basis result.	cspec PMID:18809606
BP6	N/A	Not applicable: the MSH6 VCEP explicitly prohibits BP6, so no benign source assertion can activate this criterion.	cspec
BP7	N/A	Not applicable: c.3261dup is a coding frameshift, while BP7 is restricted to synonymous or intronic variants at or beyond -21/+7.	cspec

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