PM2_Supporting is met: the variant is absent from gnomAD v4.1 (0/1,614,568 alleles) and gnomAD v2.1, meeting the VCEP threshold of allele frequency <0.00002.1 PP3_Moderate is met: the HCI prior probability of pathogenicity for c.3412G>A (p.G1138R) is 0.9617, exceeding the VCEP PP3_Moderate threshold of >0.81. REVEL score is 0.947, consistent with a deleterious prediction.2 PVS1 is not applicable: this is a missense variant (p.Gly1138Arg), not a null variant, and SpliceAI predicts no splice impact (max delta = 0.01).3 PS3 is not met: no calibrated functional assay data exists for p.Gly1138Arg in the VCEP functional assay documentation or published literature.4 PS1, PS2, PM5, PP1, PP4, BA1, BS1, BS2, BS3, BS4, BP4, BP5 are not met due to absence of supporting evidence.5 PS4, PS5, PM1, PM6, PP2, PP5, BP1, BP2, BP3, BP6, BP7, PM3, PM4 are not applicable per the InSiGHT MMR VCEP v2.0.0 specifications or because the variant class does not meet the criterion definition.6
MSH6
Final classification
VUS
MSH6 c.3412G>A · p.Gly1138Arg
MSH6
PM2_Supporting is met: the variant is absent from gnomAD v4.1 (0/1,614,568 alleles) and gnomAD v2.1, meeting the VCEP threshold of 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, PP3 moderate; no rule matched the adjudicated criteria.
Classification rationale
PM2PP3
VUS
MSH6 c.3412G>A
PM2 + PP3
→
VUS
Gene diagram
· NM_000179.2 · variants mapped to exon structure
MSH6
NM_000179.2
Fetching transcript structure from UCSC…
Applied criteria · 2 applied · 13 assessed
Applied · 2
Strength
Supporting
Moderate
Strong
Very strong
✓
PM2
supporting
Pathogenic
The variant is absent from gnomAD v4.1 (0 alleles across 1,614,568 total alleles) and gnomAD v2.1. This meets the VCEP PM2_Supporting threshold of allele frequency <0.00002 (<1 in 50,000 alleles).
Absent from gnomAD v4.1 (0/1614568 alleles
✓
PP3
moderate
Pathogenic
The HCI prior probability of pathogenicity for c.3412G>A (p.G1138R) is 0.9617, which exceeds the VCEP PP3_Moderate threshold of >0.81. REVEL score is 0.947, consistent with a deleterious prediction.
HCI prior probability = 0.9617 (>0.81 threshold for PP3_Moderate)REVEL = 0.947BayesDel = 0.451.
Assessed · not applied
Pathogenic
PS1
No different nucleotide change encoding the same amino acid (p.Gly1138Arg) has been established as Pathogenic by the InSiGHT MMR VCEP.
PS2
No de novo occurrence has been reported for this variant.
PS3
No calibrated functional assay data exists for p.Gly1138Arg.
PM5
No alternate missense change at codon 1138 has been classified as Pathogenic or Likely Pathogenic by the InSiGHT MMR VCEP.
PP1
No co-segregation data with a combined Bayes Likelihood Ratio has been reported for this variant.
PP4
No MSI-H tumor data or MMR protein expression data (IHC) specific to this variant has been reported.
Benign
BA1
The variant is absent from gnomAD v4.1 (0 alleles).
BS1
The variant is absent from gnomAD v4.1.
BS2
No evidence of co-occurrence in trans with a known pathogenic MSH6 variant in a patient with colorectal cancer after age 45 without CMMRD features has been reported.
BS3
No calibrated functional assay data showing a benign effect (functional odds for pathogenicity ≤ 0.05 for Strong or ≤ 0.48 for Supporting) exists for p.Gly1138Arg.
BS4
No lack-of-segregation data with a combined Bayes Likelihood Ratio has been reported for this variant.
BP4
The HCI prior probability of pathogenicity for c.3412G>A is 0.9617, which is far above the VCEP BP4_Supporting threshold of <0.11.
BP5
No tumor data demonstrating MSS status or BRAF V600E/MLH1 methylation has been reported for patients carrying this variant.
N/A · 13
PVS1 · PS4 · PM1 · PM3 · PM4 · PM6 · PP2 · PP5 · BP1 · BP2 · BP3 · 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
Absent from gnomAD-Canada v1.0.
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 = 650516)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.947. BayesDel score = 0.451433. HCI prior probability for pathogenicity = 0.9617. MAPP score = 36.52. Custom PP2 score = 0.999.
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
9Sources
Triaged references · 2 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
28492532 ↗
Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.
CLINVAR