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 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
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