NM_000179.3:c.836G>A (p.Ser279Asn) is a missense variant in MSH6 exon 4 that is absent from gnomAD v2.1 and v4.1, meeting the VCEP PM2_Supporting criterion (allele frequency <0.00002).1 Computational in silico predictors, including the MSH6-specific HCI prior probability of 0.0075, are consistent with a benign impact, meeting the VCEP BP4_Supporting criterion (HCI prior <0.11). SpliceAI predicts no splicing alteration (max delta score 0.00). REVEL score is 0.322 and BayesDel is -0.109.2 No functional assay data, segregation data, de novo observations, tumor phenotype data, or same-residue pathogenic comparator variants are available for this variant. The variant has been reported in ClinVar as Uncertain significance (2 clinical laboratories; ClinVar ID 234915) and has been observed once in somatic cancers (COSMIC COSV113286823).3 Per the MSH6 VCEP v2.0.0 combination rules: PM2_Supporting (1 pathogenic supporting point) and BP4_Supporting (1 benign supporting point) are equivocal, resulting in a final classification of Uncertain Significance (VUS).4
MSH6
Final classification
VUS
MSH6 c.836G>A · p.Ser279Asn
MSH6
NM_000179.3:c.836G>A (p.Ser279Asn) is a missense variant in MSH6 exon 4 that is absent from gnomAD v2.1 and v4.1, meeting the VCEP PM2_Supporting criterion (allele frequency <0.00002).
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 was evaluated deterministically with applied criteria: PM2 supporting, BP4 supporting benign; no rule matched the adjudicated criteria.
Classification rationale
PM2
BP4
VUS
MSH6 c.836G>A
PM2 + BP4
→
VUS
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
Applied · 2
Strength
Supporting
Moderate
Strong
Very strong
✓
PM2
supporting
Pathogenic
Absent from gnomAD v4.1 (0 alleles), meeting the MSH6 VCEP PM2_Supporting allele frequency threshold of <0.00002 (<1 in 50,000 alleles).
gnomAD v2.1: absentgnomAD v4.1: absent. Allele frequency 0.0below VCEP PM2_Supporting cutoff of 0.00002.
✓
BP4
supporting
Benign
HCI prior probability for pathogenicity is 0.0075, which is below the MSH6 VCEP BP4_Supporting threshold of <0.11 for missense variants. Multiple lines of computational evidence suggest no deleterious impact.
HCI prior: 0.0075 (<0.11 BP4_Supporting threshold). SpliceAI max delta: 0.00 (no splicing impact). REVEL: 0.322. BayesDel: -0.109.
Assessed · not applied
Pathogenic
PS1
No alternate nucleotide change at codon 279 encoding p.Ser279Asn has been classified as Pathogenic by the MSH6 VCEP.
PS2
No de novo occurrences with confirmed parentage have been reported for NM_000179.3:c.836G>A.
PS3
No calibrated functional assay data with functional odds for pathogenicity are available for this variant.
PM5
No missense variant at codon 279 has been classified as Pathogenic or Likely Pathogenic on the protein level by the MSH6 VCEP; PM5 requires an established P/LP comparator at the same residue.
PP1
No cosegregation data with computed Bayes Likelihood Ratio are available for this variant.
PP3
HCI prior probability 0.0075 does not meet VCEP missense thresholds (>0.68 for PP3_Supporting, >0.81 for PP3_Moderate).
PP4
No MSI-H tumor data or MMR protein expression loss data consistent with the variant location have been reported for c.836G>A.
Benign
BA1
Absent from gnomAD v4.1; does not meet the VCEP BA1 Stand-Alone threshold of Grpmax filtering AF >= 0.0022 (0.22%).
BS1
Absent from gnomAD v4.1; does not meet the VCEP BS1 Strong threshold of Grpmax filtering AF >= 0.00022 (0.022%).
BS2
No evidence of co-occurrence in trans with a known pathogenic MSH6 variant in a patient with CRC after age 45 without CMMRD features.
BS3
No calibrated functional assay data showing functional odds for pathogenicity <= 0.48 for this variant.
BS4
No lack-of-segregation data with computed Bayes Likelihood Ratio are available for this variant.
BP5
No MSS tumor data or MMR protein expression data demonstrating inconsistent MMR protein loss have been reported for this variant.
N/A · 10
PVS1 · PS4 · PM1 · PM6 · PP2 · PP5 · BP1 · BP2 · BP6 · BP7
Research & evidence
Population frequency
gnomAD v4.1
gnomAD v2.1
v4.1
Absent from gnomAD v4.1.
v2.1
Absent from gnomAD v2.1.
🇨🇦 CA
This variant is absent from gnomAD-Canada.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
gnomAD v2.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
gnomAD Canada 🇨🇦
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
ClinVar
This variant has been reported in ClinVar as Uncertain significance (2 clinical laboratories). (ClinVarID = 234915)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.322. BayesDel score = -0.109362. HCI prior probability for pathogenicity = 0.0075. MAPP score = 5.62. Custom PP2 score = 0.093.
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 previously been reported in somatic cancers (COSMIC; COSV113286823, n = 1 times).
Hotspots
This variant does not lie in a statistically significant hotspot.
Sources & reference links
Triaged references · 1 PMID 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