Classification rationale

PVS1PM2 Likely Pathogenic

MSH6 c.1569_1572del frameshift · exon 4

PVS1 very strong: the frameshift truncates MSH6 at codon 569, upstream of the InSiGHT codon 1341 boundary and predicted to undergo nonsense-mediated decay. PM2 supporting: gnomAD v4.1 total allele frequency 6.19e-07 is below the MSH6 specification's rarity threshold of 0.00002.

PVS1 + PM2 → Likely Pathogenic

LYFE Sciences is an AI system, and it can make mistakes. Criteria may be applied incorrectly, sources may be misread, and a confident-looking classification can still be wrong. Double-check every criterion and its underlying evidence before relying on any call.

Gene diagram · NM_000179.3 · variants mapped to exon structure

MSH6 NM_000179.3

Fetching transcript structure from UCSC…

Applied criteria · 2 applied · 13 assessed

MetEvidence satisfies this criterion.

Not metEvaluated against available evidence; threshold not reached.

Not assessedApplies in principle, but no evidence was found to evaluate it.

N/ADoesn't apply to this variant type.

Applied · 2

Strength Supporting Moderate Strong Very strong

PVS1 very strong Pathogenic

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.

Variant NM_000179.3:c.1569_1572del is a 4-bp deletion in MSH6 exon 4 (c.628-3172) causing an out-of-frame frameshift with a premature termination codon at codon 569 (NP_000170.1:p.(Tyr524ValfsTer46)); the predicted protein terminates at residue 569 (c.1705-1707).NM_000179.3 is the MANE Select transcript and the transcript specified by the governing MSH6 specification (raw_rule_origin preferredTranscript = NM_000179.3), so it is the clinically relevant transcript.Governing framework is the ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Expert Panel specification to the ACMG/AMP guidelines for MSH6, Version 2.0 (doc 1578294885), which takes precedence over generic ACMG/AMP defaults.

cspec ↗

PM2 supporting Pathogenic

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).

MSH6 VCEP v2.0 (cspec) PM2 rule: Absent/extremely rare allele frequency <0.00002 (<1 in 50,000 alleles) in gnomAD v4 dataset (applied strength: Supporting).gnomAD v4.1: total AF 6.19499e-07 (AC=1, AN=1,614,208, homozygotes=0); exome AF 6.84053e-07 (AC=1, AN=1,461,876).gnomAD v4.1 highest subpopulation: European (non-Finnish) AF 8.47435e-07 (AC=1, AN=1,180,032, homozygotes=0).

cspec ↗gnomad_v4 ↗gnomad_v2 ↗gnomad_canada ↗clinvar ↗

Assessed · not applied · 4 not met · 9 not assessed

Pathogenic

PS1 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.

PS2 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.

PS3 Not assessed: no variant-specific calibrated functional-odds or MMR activity result is available for this frameshift, leaving the PS3 threshold unresolved.

PM3 Not assessed: no second pathogenic MSH6 allele, CMMRD-consistent proband, or cis/trans phase evidence exists, so no PM3 points can be assigned.

PM5 Not met: c.1569_1572del is a frameshift with no missense residue context, so the same-residue missense requirement of PM5 cannot be satisfied.

PP1 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.

PP4 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.

Benign

BA1 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.

BS1 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.

BS2 Not assessed: no trans co-occurrence or phase data for a second MSH6 pathogenic variant is available to evaluate the MSH6 VCEP BS2 rule.

BS3 Not assessed: no variant-specific calibrated functional-odds or proficient-function assay result is available for this frameshift, leaving the BS3 threshold unresolved.

BS4 Not assessed: no genotyped pedigree exists, so no combined Bayes likelihood ratio could be tested against the MSH6 VCEP <=0.48 BS4 threshold.

BP5 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.

N/A · 13 PS4 · PM1 · PM4 · PM6 · PP2 · PP3 · PP5 · BP1 · BP2 · BP3 · BP4 · BP6 · BP7

Research & evidence

Population frequency · supports pathogenic

gnomAD v4.1

gnomAD v2.1

v4.1

This variant is present in gnomAD v4.1 (AF= 6.19499e-07; MAF= 0.00006%, 1/1614208 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.47435e-07; MAF= 0.00008%, 1/1180032 alleles, homozygotes = 0).

v2.1

Absent from gnomAD v2.1.

🇨🇦 CA

Absent from gnomAD-Canada v1.0.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

6.2e-05% · 1 / 1,614,208
0 hom

European (non-Finnish)

1 / 1,180,032

8.5e-05%

+ 9 not observed (Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American)

gnomAD v2.1

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD Canada 🇨🇦

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v4 ↗ gnomAD v2 ↗ gnomAD 🇨🇦 ↗

ClinVar

This variant has been reported in ClinVar as Pathogenic (3 clinical laboratories) and as Likely pathogenic (1 clinical laboratory). (ClinVarID = 1386337)

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.09).

SpliceAI ↗

Functional Likely Oncogenic

OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.

OncoKB ↗

COSMIC

Cancer hotspots

Somatic evidence Not in COSMIC / hotspots

COSMIC

This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).

Hotspots

This variant does not lie in a statistically significant hotspot.

COSMIC ↗ Hotspots ↗

Literature · how each cited paper was used

2papers cited

Each card is an audit: what was searched, what was found, whether it names the variant, which criteria it fed, and why. 5 further PMIDs triaged but not cited — see Sources & references.

Rule & framework references · cited for criterion definitions, not variant evidence

24362816 ↗ Application of a 5-tiered scheme for standardized classification of 2,360 unique mismatch repair gene variants in the InSiGHT locus-specific database.

25741868 ↗ Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Sources & reference links

9Sources

CSpec VCEP

ClinVar

gnomAD v2.1

gnomAD v4.1

gnomAD-Canada

SpliceAI

OncoKB

COSMIC

Cancer hotspots

Triaged references · 5 PMIDs not cited in assessment

1651234 ↗ Altering the conserved nucleotide binding motif in the Salmonella typhimurium MutS mismatch repair protein affects both its ATPase and mismatch binding activities. ONCOKB

22810696 ↗ Comprehensive molecular characterization of human colon and rectal cancer. ONCOKB

24755471 ↗ Colorectal cancer cell lines are representative models of the main molecular subtypes of primary cancer. ONCOKB

9111312 ↗ Genetic and biochemical analysis of Msh2p-Msh6p: role of ATP hydrolysis and Msh2p-Msh6p subunit interactions in mismatch base pair recognition. ONCOKB

18269114 ↗ Germline MSH6 mutations are more prevalent in endometrial cancer patient cohorts than hereditary non polyposis colorectal cancer cohorts. CLINVAR

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