Classification rationale

PM2 BP4 VUS

MSH6 c.2975A>G missense · exon 4

PM2 (Supporting): gnomAD v4.1 total allele frequency 1.91e-06 (3/1,567,038 alleles), below the VCEP 0.00002 threshold. BP4 (Supporting): HCI-prior pathogenicity probability 0.0276, below the VCEP 0.11 threshold. Overall: VUS — one supporting pathogenic-direction and one supporting benign-direction criterion meet VCEP Rule31 (conflicting evidence), mapped to VUS.

PM2 + BP4 → VUS

Gene diagram · NM_000179.2 · variants mapped to exon structure

MSH6 NM_000179.2

Fetching transcript structure from UCSC…

Applied criteria · 2 applied · 14 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

✓

PM2 supporting Pathogenic

Met (Supporting): gnomAD v4.1 total allele frequency 1.91e-06 (3/1,567,038 alleles), below the VCEP 0.00002 threshold.

The MSH6 InSiGHT VCEP Version 2.0 rule assigns PM2 Supporting when the allele frequency is <0.00002 (<1 in 50,000 alleles) in gnomAD v4.gnomAD v4.1 reports total AF 1.91444e-06 (3 alternate alleles among 1,567,038 alleles), below 0.00002; the highest reported population AF is 3.31246e-05 in the Remaining individuals population, but this is a population-specific observation and does not replace the reported total AF for the VCEP PM2 threshold.The gnomAD v4 record reports one homozygote; no individual-level phenotype, age, penetrance, phase, or CMMRD information is provided to convert that observation into BS2 evidence.

cspec ↗gnomad_v4 ↗

✓

BP4 supporting Benign

Met (Supporting): HCI-prior pathogenicity probability 0.0276, below the VCEP BP4 supporting threshold of <0.11.

VCEP HCI-PRIORS-MSH6.txt lookup guidance: BP4_Supporting when HCI prior probability for pathogenicity <0.11.hci_prior lookup for c.2975A>G (protein p.E992G): probability = 0.0276, which is <0.11, meeting the BP4_Supporting threshold.cspec BP4 rule text: 'Missense variant with HCI-prior probability of pathogenicity <0.11 ... OR For intronic and synonymous variants: SpliceAI predicts no splicing impact with delta score <= 0.1' — the missense/HCI branch is the applicable one here.

cspec ↗

Assessed · not applied · 4 not met · 10 not assessed

Pathogenic

PS1 Insufficient evidence was available to confirm or exclude an alternate codon producing p.Glu992Gly that was previously classified pathogenic.

PS2 Insufficient evidence: no documented de novo occurrence with proband status, parental testing, or confirmed maternity and paternity.

PS3 Insufficient evidence: no variant-specific functional assay, RNA, or monoallelic-expression data; two ClinVar submissions report no published functional studies.

PM3 Insufficient evidence: no second pathogenic MSH6 variant or documented phase from family testing to assess co-occurrence.

PM5 Not met: no same-residue (codon 992) pathogenic comparator was identified, and PP3 is not met for p.Glu992Gly.

PP1 Insufficient evidence: no segregation data, pedigree, or informative meioses from affected family members.

PP3 Not met: HCI-prior pathogenicity probability 0.0276, below the PP3 supporting threshold of >0.68.

PP4 Insufficient evidence: no patient-specific MSI-H tumor or MMR immunohistochemistry result consistent with the variant's location.

Benign

BA1 Not met: gnomAD v4.1 allele frequency 1.91e-06, far below the BA1 threshold of at least 0.0022.

BS1 Not met: gnomAD v4.1 allele frequency 1.91e-06, below the BS1 strong threshold of at least 0.00022.

BS2 Insufficient evidence: no individual-level data on in-trans co-occurrence with a pathogenic variant, cancer age, or phase confirmation.

BS3 Insufficient evidence: no variant-specific functional assay data (calibrated odds or proficient-function assay results).

BS4 Insufficient evidence: no non-segregation observations, pedigree, or Bayes likelihood ratio available.

BP5 Insufficient evidence: no patient-specific tumor results (MSS, MMR loss patterns, or BRAF V600E/MLH1 methylation).

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= 1.91444e-06; MAF= 0.00019%, 3/1567038 alleles, homozygotes = 1) and has highest observed frequency in the Remaining individuals population (AF= 3.31246e-05; MAF= 0.00331%, 2/60378 alleles, homozygotes = 1).

v2.1

This variant is present in gnomAD v2.1 (AF= 4.69598e-06; MAF= 0.00047%, 1/212948 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 9.93029e-06; MAF= 0.00099%, 1/100702 alleles, homozygotes = 0).

🇨🇦 CA

Not available in gnomAD-Canada v1.0.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

0.00019% · 3 / 1,567,038
1 hom

Remaining individuals 2 / 60,378	0.0033% 1 hom
European (non-Finnish) 1 / 1,158,854	8.6e-05%

+ 8 not observed (Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American)

gnomAD v2.1

0.00047% · 1 / 212,948
0 hom

European (non-Finnish)

1 / 100,702

0.00099%

+ 7 not observed (African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), 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 (4 clinical laboratories) and as Likely benign (1 clinical laboratory) and as Uncertain Significance (1 clinical laboratory). (ClinVarID = 233859)

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.458. BayesDel score = -0.0480668. HCI prior probability for pathogenicity = 0.0276. MAPP score = 11.35. Custom PP2 score = 0.029.

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

25394175 ↗ A practice guideline from the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors: referral indications for cancer predisposition assessment. CLINVAR

25452455 ↗ Hereditary colorectal cancer syndromes: American Society of Clinical Oncology Clinical Practice Guideline endorsement of the familial risk-colorectal cancer: European Society for Medical Oncology Clinical Practice Guidelines. CLINVAR

25741868 ↗ Standards and guidelines for the interpretation of sequence variants: a joint co CLINVAR

26389210 ↗ Genetics of Breast and Gynecologic Cancers (PDQ®): Health Professional Version. CLINVAR

26389258 ↗ Cancer Genetics Risk Assessment and Counseling (PDQ®): Health Professional Versi CLINVAR

28492532 ↗ Sherloc: a comprehensive refinement of the ACMG-AMP variant classification crite CLINVAR

31159747 ↗ Analysis of hereditary cancer syndromes by using a panel of genes: novel and multiple pathogenic mutations. CLINVAR

33451724 ↗ Endometrial cancer: A society of gynecologic oncology evidence-based review and CLINVAR