LYFE Sciences · Project HERA
Variant Interpretation · Classification Report
Generated: 2026-10-07
Case ID: NM_000179.3_c.1569_1572del_20261007_195345
Framework: ACMG/AMP 2015
Variant classification summary

NM_000179.3:c.1569_1572del

MSH6  · NP_000170.1:p.(Tyr524ValfsTer46)  · NM_000179.3
GRCh37: chr2:48026688 GACTT>G  ·  GRCh38: chr2:47799549 GACTT>G
Gene: MSH6 Transcript: NM_000179.3
Final call
Likely Pathogenic
PVS1 very strong PM2 supporting
All criteria require review: For research and educational purposes only.
Variant details
Gene
MSH6
Transcript
NM_000179.3
Protein
NP_000170.1:p.(Tyr524ValfsTer46)
gnomAD AF
6.19498850210134e-07 (v4.1)
ClinVar
Pathogenic
OncoKB
Likely Oncogenic
Classification rationale
Interpretation summary
Generated evidence synthesis
1
PVS1 very strong: the frameshift truncates MSH6 at codon 569, upstream of the InSiGHT codon 1341 boundary and predicted to undergo nonsense-mediated decay.
2
PM2 supporting: gnomAD v4.1 total allele frequency 6.19e-07 is below the MSH6 specification's rarity threshold of 0.00002.
Final determination: In the ClinGen InSiGHT MSH6 specification's Richards et al., 2015 combining rules, one Pathogenic.Very Strong criterion together with one Pathogenic.Supporting criterion (here PVS1 very strong and PM2 supporting) is classified as Likely Pathogenic.
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 at very strong: the frameshift introduces a PTC at codon 569, upstream of the MSH6 codon 1341 InSiGHT very-strong threshold and predicted to trigger NMD.
cspec vcep_pvs1_decisiontree_mmr vcep_mmr_functional_domains pvs1_variant_assessment pvs1_gene_context gnomad_v4 spliceai clinvar oncokb PMID:25741868 PMID:24362816
PS1 Not met Not met: c.1569_1572del is a frameshift (p.Tyr524ValfsTer46), not a missense substitution, so the same-amino-acid-change requirement of PS1 cannot be satisfied.
cspec
PS2 Not assessed Not assessed: no proband, parental testing or de novo occurrence is documented, so no MSH6 VCEP de novo points (0.5 to >=4) could be counted.
cspec PMID:25741868
PS3 Not assessed Not assessed: no variant-specific calibrated functional-odds or MMR activity result is available for this frameshift, leaving the PS3 threshold unresolved.
cspec vcep_functional_assay_svi_documentation_mmr vcep_functional_assay_flowchart vcep_mmr_functional_domains vcep_pvs1_decisiontree_mmr PMID:24362816 PMID:25741868 PMID:9111312 PMID:22810696 PMID:24755471 PMID:1651234
PS4 N/A Not applicable: the governing MSH6 v2.0 specification disables PS4 and no case-control enrichment data exist for c.1569_1572del.
cspec
PM1 N/A Not applicable: the governing MSH6 v2.0 specification lists PM1 as Not Applicable, and vcep_materials.json contains no domain_tables entry for MSH6.
cspec vcep_mmr_functional_domains
PM2 Met Met (Supporting): gnomAD v4.1 total AF 6.19e-07 is below the MSH6 VCEP PM2 threshold of <0.00002 (<1 in 50,000 alleles).
cspec gnomad_v4 gnomad_v2 gnomad_canada clinvar
PM3 Not assessed Not assessed: no second pathogenic MSH6 allele, CMMRD-consistent proband, or cis/trans phase evidence exists, so no PM3 points can be assigned.
cspec clinvar
PM4 N/A Not applicable: the InSiGHT MSH6 v2.0 specification marks PM4 not applicable, and this is an out-of-frame frameshift rather than an in-frame length-change variant.
cspec pvs1_variant_assessment
PM5 Not met Not met: c.1569_1572del is a frameshift with no missense residue context, so the same-residue missense requirement of PM5 cannot be satisfied.
cspec pm5_candidates
PM6 N/A Not applicable: the governing MSH6 VCEP v2.0 specification marks PM6 Not Applicable, so assumed-de-novo evidence is scored under PS2 instead.
cspec PMID:25741868
PP1 Not assessed Not assessed: no pedigree or meiosis data exist, so no combined Bayes likelihood ratio could be tested against the MSH6 VCEP >2.08 PP1 threshold.
cspec PMID:24362816 PMID:25741868
PP2 N/A Not applicable: the governing MSH6 v2.0 specification lists PP2 as Not Applicable, and the variant is a frameshift rather than a missense.
cspec
PP3 N/A Not applicable: PP3 is scoped to missense or splice-region variants, and this is a frameshift (p.Tyr524ValfsTer46).
cspec
PP4 Not assessed Not assessed: no tumor MSI or MMR-IHC data exist for this case, so PP4's requirement of at least one MSI-H CRC/endometrial tumor cannot be evaluated.
cspec
PP5 N/A Not applicable: the governing MSH6 v2.0 specification disables PP5 and the ClinVar record has no expert-panel classification of this exact variant.
cspec clinvar
BA1 Not met Not met: gnomAD v4.1 total AF 6.19e-07 (popmax NFE 8.47e-07) is far below the MSH6 VCEP BA1 threshold of >=0.0022.
cspec gnomad_v4 gnomad_v2 gnomad_canada
BS1 Not met Not met: gnomAD v4.1 total AF 6.19e-07 (popmax NFE 8.47e-07) is below the MSH6 VCEP BS1 lower bound of >=0.00022.
cspec gnomad_v4 gnomad_v2 gnomad_canada
BS2 Not assessed Not assessed: no trans co-occurrence or phase data for a second MSH6 pathogenic variant is available to evaluate the MSH6 VCEP BS2 rule.
cspec
BS3 Not assessed Not assessed: no variant-specific calibrated functional-odds or proficient-function assay result is available for this frameshift, leaving the BS3 threshold unresolved.
cspec vcep_functional_assay_svi_documentation_mmr vcep_functional_assay_flowchart vcep_mmr_functional_domains vcep_pvs1_decisiontree_mmr PMID:24362816 PMID:25741868 PMID:9111312 PMID:22810696 PMID:24755471 PMID:1651234
BS4 Not assessed Not assessed: no genotyped pedigree exists, so no combined Bayes likelihood ratio could be tested against the MSH6 VCEP <=0.48 BS4 threshold.
cspec PMID:25741868
BP1 N/A Not applicable: the governing MSH6 v2.0 specification lists BP1 as Not Applicable, and the variant is a frameshift rather than a missense.
cspec
BP2 N/A Not applicable: the ClinGen InSiGHT MSH6 v2.0 specification designates BP2 as Not applicable, directing use of BS2 instead.
cspec
BP3 N/A Not applicable: the InSiGHT MSH6 v2.0 specification marks BP3 not applicable, and this out-of-frame frameshift is not an in-frame repeat-region indel.
cspec pvs1_variant_assessment
BP4 N/A Not applicable: BP4 is scoped to missense or intronic/synonymous variants, and this is a frameshift (p.Tyr524ValfsTer46).
cspec
BP5 Not assessed Not assessed: no tumor MSI, MMR-IHC, BRAF V600E or MLH1 methylation data exist, so BP5's ≥2 MSS/no-MMR-loss tumor requirement cannot be evaluated.
cspec
BP6 N/A Not applicable: the governing MSH6 v2.0 specification disables BP6 and no expert panel has classified this variant benign or likely benign.
cspec clinvar
BP7 N/A Not applicable: BP7 requires a synonymous or intronic variant, and this is a frameshift (p.Tyr524ValfsTer46).
cspec
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