The MSH6 c.866G>A (p.Gly289Asp; p.G289D) variant has not been observed in COSMIC and has been reported in ClinVar with conflicting germline classifications, including uncertain significance, likely benign, and benign submissions.1 This variant is present in gnomAD v4.1 at an allele frequency of 0.000216846 (350/1614052 alleles) with grpmax filtering allele frequency 0.00024593, which exceeds the MSH6 BS1 threshold of 0.00022 but remains below the BA1 threshold of 0.0022.2 Computational data support a benign interpretation: the MSH6 HCI prior probability is 0.0021, below the BP4 threshold of 0.11, SpliceAI predicts no significant splice impact with a max delta score of 0.01, and additional predictors are not strongly damaging (REVEL 0.272; BayesDel -0.256015).3
MSH6
Final classification
Likely Benign
MSH6 c.866G>A · p.Gly289Asp
MSH6
The MSH6 c.866G>A (p.Gly289Asp; p.G289D) variant has not been observed in COSMIC and has been reported in ClinVar with conflicting germline classifications, including uncertain significance, likely benign, and benign submissions.
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: matched Rule18 (1 Benign.Strong + 1 Benign.Supporting) with applied criteria: BS1 strong, BP4 supporting; maps to Likely Benign.
Classification rationale
BS1BP4
Likely Benign
MSH6 c.866G>A
BS1 + BP4
→
Likely Benign
Gene diagram
· NM_000179.3 · variants mapped to exon structure
MSH6
NM_000179.3
Fetching transcript structure from UCSC…
Applied criteria · 2 met · select any tile
Met
Not met
Not assessed
N/A
Strength
very strong
supporting
Pathogenic evidence
PVS
PS
PM
PP
Benign evidence
BA
BS
BP
—
—
—
Rationale
Select a criterion.
Sources
Evidence used
Gaps remaining
Rule
—
Research & evidence
Population frequency · supports benign
gnomAD v4.1
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 0.000216846; MAF= 0.02168%, 350/1614052 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 0.00040009; MAF= 0.04001%, 25/62486 alleles, homozygotes = 0); grpmax FAF= 0.00024593.
v2.1
This variant is present in gnomAD v2.1 (AF= 9.20165e-05; MAF= 0.00920%, 26/282558 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 0.000193865; MAF= 0.01939%, 25/128956 alleles, homozygotes = 0); grpmax FAF= 0.00012357.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.022%
· 350 / 1,614,052
0 hom · FAF 0.025%
0 hom · FAF 0.025%
Remaining individuals 25 / 62,486 |
0.04% |
European (non-Finnish) 320 / 1,180,044 |
0.027% |
African/African American 5 / 74,920 |
0.0067% |
+ 7 not observed (Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish)
gnomAD v2.1
0.0092%
· 26 / 282,558
0 hom · FAF 0.012%
0 hom · FAF 0.012%
European (non-Finnish) 25 / 128,956 |
0.019% |
African/African American 1 / 24,928 |
0.004% |
+ 6 not observed (Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals, South Asian)
ClinVar
This variant has been reported in ClinVar as Uncertain significance (3 clinical laboratories) and as Benign (1 clinical laboratory) and as Likely benign (1 clinical laboratory). (ClinVarID = 627661)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.272. BayesDel score = -0.256015. HCI prior probability for pathogenicity = 0.0021. MAPP score = 3.78. Custom PP2 score = 0.001.
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.
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.
Sources & reference links
Triaged references · 9 PMIDs not cited in assessment
16010685 ↗
Rapid recognition of aberrant dHPLC elution profiles using the Transgenomic Navigator software.
CLINVAR
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.
CLINVAR
26898890 ↗
Prioritizing Variants in Complete Hereditary Breast and Ovarian Cancer Genes in Patients Lacking Known BRCA Mutations.
CLINVAR
18269114 ↗
Germline MSH6 mutations are more prevalent in endometrial cancer patient cohorts than hereditary non polyposis colorectal cancer cohorts.
CLINVAR
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
28767289 ↗
Deleterious Germline Mutations in Patients With Apparently Sporadic Pancreatic Adenocarcinoma.
CLINVAR
28492532 ↗
Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.
CLINVAR