Classification rationale

BP4 VUS

MSH6 c.1474A>G missense · exon 4

BP4 supporting: the VCEP HCI prior probability is 0.0086, below the <0.11 threshold.

BP4 → VUS

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 · 1 applied · 15 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 · 1

Strength Supporting Moderate Strong Very strong

BP4 supporting Benign

Met, Supporting: the governing HCI prior probability is 0.0086, below the BP4 threshold of <0.11.

The MSH6 VCEP specification defines BP4_Supporting for missense variants with HCI prior probability <0.11.The exact HCI-PRIORS-MSH6 entry for c.1474A>G (p.M492V) reports pathogenicity probability 0.0086, which meets the governing BP4 threshold.Because the governing VCEP provides an exact pre-assigned HCI prior result, it is applied directly and no additional predictor is combined with it.

cspec ↗

Assessed · not applied · 6 not met · 9 not assessed

Pathogenic

PS1 Not met: no qualifying alternate nucleotide change encoding the same p.Met492Val substitution was established as Pathogenic by the MSH6 VCEP.

PS2 Not assessed: no documented de novo status, confirmed maternity and paternity, or qualifying MMR-deficient tumor is available for the proband.

PS3 Not met: cell-free mismatch-repair testing found p.Met492Val repair proficient, with no calibrated pathogenicity odds supporting PS3.

PM2 Not met: gnomAD v4.1 total allele frequency is 0.000101608, exceeding the MSH6 PM2 threshold of 0.00002.

PM3 Not assessed: no pathogenic second MSH6 variant, CMMRD phenotype, or parent/offspring-confirmed phase is documented for the reported p.Met492Val observations.

PM5 Not assessed: no qualifying alternate missense comparator at MSH6 residue 492 was available, and the required comparator search ended with a retrieval failure.

PP1 Not assessed: p.Met492Val was reported in families, but no pedigree counts, meioses, or Bayes likelihood ratio are provided for segregation.

PP3 Not met: the governing HCI prior probability is 0.0086, below the PP3 supporting threshold of >0.68.

PP4 Not assessed: reported tumors lacked qualifying MSH6-consistent findings, while the available records do not establish a qualifying MSI-H tumor or protein-loss result.

Benign

BA1 Not met: gnomAD v4.1 grpmax filtering allele frequency is 0.00008673, below the MSH6 BA1 threshold of 0.0022.

BS1 Not met: gnomAD v4.1 grpmax filtering allele frequency is 0.00008673, below the MSH6 BS1 lower threshold of 0.00022.

BS2 Not assessed: no documented qualifying in-trans pathogenic variant, cancer-age criterion, CMMRD assessment, and confirmed phase are available for MSH6 BS2.

BS3 Not assessed: p.Met492Val was repair proficient in one assay, but calibrated odds and the VCEP-required concordant protein-plus-mRNA evidence are unavailable.

BS4 Not assessed: no affected non-carriers, pedigree-level non-segregation analysis, or Bayes likelihood ratio is reported.

BP5 Not assessed: no qualifying set of at least 2 exact-variant-associated tumors meeting the MSH6 BP5 benign-pattern rule is documented.

N/A · 12 PVS1 · PS4 · PM1 · PM4 · PM6 · PP2 · PP5 · BP1 · BP2 · BP3 · BP6 · BP7

Research & evidence

Population frequency

gnomAD v4.1

gnomAD v2.1

v4.1

This variant is present in gnomAD v4.1 (AF= 0.000101608; MAF= 0.01016%, 164/1614046 alleles, homozygotes = 0) and has highest observed frequency in the European (Finnish) population (AF= 0.000577818; MAF= 0.05778%, 37/64034 alleles, homozygotes = 0); grpmax FAF= 8.673e-05.

v2.1

This variant is present in gnomAD v2.1 (AF= 8.13952e-05; MAF= 0.00814%, 23/282572 alleles, homozygotes = 0) and has highest observed frequency in the European (Finnish) population (AF= 0.000477745; MAF= 0.04777%, 12/25118 alleles, homozygotes = 0); grpmax FAF= 4.745e-05.

🇨🇦 CA

Absent from gnomAD-Canada v1.0.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

0.01% · 164 / 1,614,046
0 hom · FAF 0.0087%

European (Finnish) 37 / 64,034	0.058%
European (non-Finnish) 120 / 1,180,032	0.01%
Remaining individuals 6 / 62,488	0.0096%
African/African American 1 / 74,916	0.0013%

+ 6 not observed (Admixed American, Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish)

gnomAD v2.1

0.0081% · 23 / 282,572
0 hom · FAF 0.0047%

European (Finnish) 12 / 25,118	0.048%
European (non-Finnish) 10 / 128,940	0.0078%
African/African American 1 / 24,962	0.004%

+ 5 not observed (Admixed American, Ashkenazi Jewish, East Asian, Remaining individuals, South Asian)

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 Uncertain significance (9 clinical laboratories) and as Likely benign (3 clinical laboratories) and as Benign (1 clinical laboratory) and as Uncertain Significance (1 clinical laboratory). (ClinVarID = 89195)

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.825. BayesDel score = 0.176451. HCI prior probability for pathogenicity = 0.0086. MAPP score = 5.63. Custom PP2 score = 0.123.

SpliceAI ↗

Functional Unknown Oncogenic Effect

OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. MSH6, a DNA mismatch repair protein, is frequently mutated in colorectal, small bowel, and endometrial cancers.

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 ↗

Sources & reference links

9Sources

CSpec VCEP

ClinVar

gnomAD v2.1

gnomAD v4.1

gnomAD-Canada

SpliceAI

OncoKB

COSMIC

Cancer hotspots

Triaged references · 8 PMIDs not cited in assessment

12658575 ↗ Molecular analysis of hereditary nonpolyposis colorectal cancer in the United States: high mutation detection rate among clinically selected families and characterization of an American founder genomic deletion of the MSH2 gene. CLINVAR

17060676 ↗ ASCO 2006 update of recommendations for the use of tumor markers in gastrointest CLINVAR

18163131 ↗ The emerging landscape of breast cancer susceptibility. CLINVAR

18566915 ↗ Major contribution from recurrent alterations and MSH6 mutations in the Danish Lynch syndrome population. CLINVAR

22102614 ↗ A rapid and cell-free assay to test the activity of lynch syndrome-associated MSH2 and MSH6 missense variants. CLINVAR

22495361 ↗ MSH6 mutations are frequent in hereditary nonpolyposis colorectal cancer families with normal pMSH6 expression as detected by immunohistochemistry. CLINVAR

23047549 ↗ Frequency of mutations in mismatch repair genes in a population-based study of women with ovarian cancer. CLINVAR

23188549 ↗ NSGC practice guideline: risk assessment and genetic counseling for hereditary b CLINVAR

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