LYFE Sciences · Project HERA
Variant Interpretation · Classification Report
Generated: 2026-05-26
Case ID: NM_000179.3_c.3261del_20260526_144931
Framework: ACMG/AMP 2015
Variant classification summary

NM_000179.3:c.3261del

MSH6  · NP_000170.1:p.(Phe1088SerfsTer2)  · NM_000179.3
GRCh37: chr2:48030639 AC>A  ·  GRCh38: chr2:47803500 AC>A
Gene: MSH6 Transcript: NM_000179.3
Final call
Pathogenic
PVS1 very strong PM2 supporting PP5 supporting
All criteria require review: For research and educational purposes only.
Variant details
Gene
MSH6
Transcript
NM_000179.3
Protein
NP_000170.1:p.(Phe1088SerfsTer2)
gnomAD AF
1.428548358846379e-05 (v4.1)
ClinVar
Pathogenic
OncoKB
Likely Oncogenic
Classification rationale
Interpretation summary
Generated evidence synthesis
1
The MSH6 NM_000179.3:c.3261del (NP_000170.1:p.(Phe1088SerfsTer2)) variant has been observed in somatic cancers in COSMIC (COSV52273658, n=132) and has been reported in ClinVar as Pathogenic, including an expert-panel assertion.
2
This variant is present at extremely low frequency in population databases, with gnomAD v4.1 allele frequency 1.42855e-05 (23/1610026 alleles; grpmax FAF 7.65e-06), which is below the MSH6 VCEP PM2 threshold of 0.00002, and it is absent from gnomAD-Canada v1.0.
3
This frameshift deletion is predicted to truncate MSH6 at codon 1088, and the active MSH6 VCEP specification applies PVS1 at Very Strong strength to nonsense or frameshift variants introducing a premature termination codon at or before codon 1341.
Final determination: Rule4 in the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for MSH6 Version 2.0.0 v2.0.0 criteria-combination framework is satisfied by the adjudicated criteria, so the variant is classified as 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 This variant is a frameshift deletion predicted to produce p.(Phe1088SerfsTer2). Under the MSH6 VCEP specification, nonsense/frameshift variants introducing a premature termination codon at or before codon 1341 meet PVS1 at Very Strong strength; this variant truncates the protein at codon 1088 and loss of function is an established disease mechanism for MSH6.
cspec pvs1_gene_context pvs1_variant_assessment
PM2 Met This variant is present at extremely low frequency in population databases. In gnomAD v4.1, the allele frequency is 1.42855e-05 (23/1610026 alleles) with grpmax FAF 7.65e-06, which is below the MSH6 VCEP PM2 threshold of 0.00002 (<1 in 50,000 alleles), and it is absent from gnomAD-Canada v1.0.
cspec gnomad_v4 gnomad_canada gnomad_v2
BA1 Not met This variant does not meet BA1 because the gnomAD v4.1 filtering allele frequency is far below the MSH6 VCEP BA1 threshold of 0.0022 (0.22%).
cspec gnomad_v4
BS1 Not met This variant does not meet BS1 because the gnomAD v4.1 filtering allele frequency is below the MSH6 VCEP BS1 range of 0.00022 to <0.0022.
cspec gnomad_v4
BS2 Not assessed No confirmed in trans co-occurrence with a known pathogenic MSH6 variant in an individual meeting the VCEP age and CMMRD exclusion requirements was identified.
cspec vcep_table_for_cmmrd_diagnosis
BS3 Not assessed No directly reviewed calibrated functional assay or RNA study demonstrating normal MSH6 function for this variant was identified.
cspec vcep_functional_assay_flowchart vcep_functional_assay_svi_documentation_mmr
BS4 Not assessed No segregation dataset with a combined Bayes likelihood ratio supporting lack of co-segregation was identified.
cspec PMID:20028993
BP1 N/A BP1 is not used in the MSH6 VCEP framework.
cspec
BP2 N/A BP2 is not used in the MSH6 VCEP framework.
cspec
BP3 N/A BP3 is not used in the MSH6 VCEP framework.
cspec
BP4 N/A BP4 was not applied because the MSH6 VCEP BP4 rule is limited to missense variants with HCI prior probability <0.11 or to synonymous/intronic variants with SpliceAI <=0.1. This variant is a frameshift deletion, so those computational rules do not apply.
cspec spliceai vcep_hci_priors_msh6
BP5 Not assessed No tumor series showing repeated mismatch between the tumor phenotype and the gene harboring this variant was identified.
cspec
BP6 N/A BP6 is not used in the MSH6 VCEP framework.
cspec
BP7 N/A BP7 was not applied because this variant is not a synonymous or sufficiently deep intronic change.
cspec
PP1 Not assessed No segregation dataset with a combined Bayes likelihood ratio meeting PP1 thresholds was identified.
cspec PMID:20028993
PP2 N/A PP2 is not used in the MSH6 VCEP framework.
cspec
PP3 N/A PP3 was not applied because the MSH6 VCEP PP3 rule is limited to missense variants with qualifying HCI prior scores or non-canonical splice variants with SpliceAI >=0.2. This variant is a frameshift deletion, and the observed SpliceAI max delta score is 0.04.
cspec spliceai vcep_hci_priors_msh6
PP4 Not assessed No directly reviewed tumor MSI or mismatch-repair immunohistochemistry data specific enough to assign PP4 were identified.
cspec
PP5 Met Expert panel International Society for Gastrointestinal Hereditary Tumours (InSiGHT) classified as Pathogenic.
cspec clinvar
PS1 N/A PS1 was not applied because this variant is not a missense substitution or a non-canonical splice variant eligible for the MSH6 VCEP PS1 rule.
cspec
PS2 Not assessed No confirmed de novo occurrence with verified parentage was identified.
cspec
PS3 Not assessed No directly reviewed calibrated functional assay or RNA evidence demonstrating an abnormal MSH6 effect for this exact variant was identified for PS3 assignment.
cspec vcep_functional_assay_flowchart vcep_functional_assay_svi_documentation_mmr oncokb PMID:15837969 PMID:21674763
PS4 N/A PS4 is not used in the MSH6 VCEP framework.
cspec
PM1 N/A PM1 is not used in the MSH6 VCEP framework.
cspec
PM3 Not assessed No phase-confirmed biallelic observations or PM3 point-based evidence were identified.
cspec vcep_table_for_cmmrd_diagnosis
PM4 N/A PM4 is not used in the MSH6 VCEP framework.
cspec
PM5 N/A PM5 was not applied because the MSH6 VCEP PM5 rule is a classic same-residue missense rule, and this variant is a frameshift deletion rather than a missense change.
cspec pm5_candidates
PM6 N/A PM6 is not used in the MSH6 VCEP framework.
cspec
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