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
Final classification
Likely Benign
BS1BP4
MSH6
c.866G>A
p.Gly289Asp
This variant
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
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 · 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 · 2
Strength
Supporting
Moderate
Strong
Very strong
BS1
strong
review
Benign
Population frequency meets the MSH6 BS1 threshold. In gnomAD v4.1, the grpmax filtering allele frequency is 0.00024593, which is above the BS1 threshold of 0.00022 and below the BA1 threshold of 0.0022.
gnomAD v4.1 grpmax FAF 0.00024593MSH6 BS1 threshold 0.00022MSH6 BA1 threshold 0.0022
BP4
supporting
review
Benign
Computational evidence supports a benign interpretation. For this MSH6 missense variant, the HCI prior probability is 0.0021, which is below the BP4 threshold of 0.11. Additional predictors do not suggest a damaging effect, with REVEL 0.272, BayesDel -0.256015, and SpliceAI max delta 0.01 indicating no significant splice impact.
HCI prior 0.0021REVEL 0.272BayesDel -0.256015
Assessed · not applied
· 4 not met · 11 not assessed
Pathogenic
PVS1
This variant is a missense substitution, p.(Gly289Asp), and does not fall into the MSH6 PVS1 null-variant categories.
PS1
No previously established pathogenic or likely pathogenic variant causing the same amino acid change by a different nucleotide change was identified in the reviewed materials.
PS2
No confirmed de novo data were identified for this variant.
PS3
No calibrated functional assay result or variant-specific mismatch repair defect meeting the MSH6 PS3 requirements was identified in the reviewed materials.
PM2
Population frequency is too high for PM2.
PM3
No qualifying in trans observations in the recessive/CMMRD framework were identified for this variant.
PM5
The MSH6 framework uses classic same-residue PM5 logic for missense variants, but no verified same-residue pathogenic or likely pathogenic comparator variant for codon 289 was identified in the reviewed materials.
PP1
No segregation data were identified for this variant, so PP1 cannot be applied.
PP3
Computational evidence does not support pathogenicity under the MSH6 missense PP3 rule.
PP4
No tumor MSI or mismatch repair immunohistochemistry findings were identified to support the MSH6 PP4 phenotype-specific rule.
Benign
BA1
Population frequency does not meet the MSH6 BA1 threshold.
BS2
No confirmed observation of this variant in trans with a known pathogenic MSH6 variant in an individual meeting the MSH6 BS2 requirements was identified.
BS3
No calibrated functional assay result or variant-specific protein and RNA assay result meeting the MSH6 BS3 requirements was identified.
BS4
No lack-of-segregation data were identified for this variant, so BS4 cannot be applied.
BP5
No tumor data were identified showing mismatch repair findings inconsistent with MSH6 involvement, so BP5 cannot be applied.
N/A · 11
PS4 · PM1 · PM4 · PM6 · PP2 · PP5 · BP1 · BP2 · BP3 · BP6 · BP7
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