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NM_000179.3:c.2294G>C
p.Cys765Ser · MSH6
ClinGen InSiGHT Hereditary Colorectal Cancer/Polyposis Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for MSH6 Version 2.0 · v2.0
0%
complete
Final classification
VUS
PM2
MSH6
c.2294G>C
p.Cys765Ser
missense · exon 4
Gene context NCBI Gene ↗ OncoKB ↗

MSH6 encodes a protein in the DNA mismatch repair system, which fixes errors made during DNA replication. Partnering with MSH2, it forms a complex that recognizes and helps correct mismatched DNA bases, keeping the genetic code stable. Inherited mutations in MSH6 cause Lynch syndrome (hereditary nonpolyposis colorectal cancer), raising the risk of colorectal, endometrial, ovarian, and other cancers, while mutations in both copies lead to constitutional mismatch repair deficiency. Because faulty mismatch repair drives tumor development and produces microsatellite instability, MSH6 acts as a tumor suppressor, and cancers with such repair defects often respond well to immune checkpoint inhibitor therapy.

This variant

MSH6 encodes a DNA mismatch-repair protein that partners with MSH2 to maintain genomic stability, and inherited MSH6 variants are associated with Lynch syndrome and related mismatch-repair deficiency conditions.

Transcript
NM_000179.3
HGVS · transcript:coding
NM_000179.3:c.2294G>C
GRCh38
chr2:47800277 G>C
GRCh37
chr2:48027416 G>C
VUS: PM2 (supporting) was the only applied criterion, and no ClinGen InSiGHT MSH6 combination rule was satisfied.
Classification rationale
PM2 VUS
MSH6 c.2294G>C missense · exon 4

PM2 Supporting: the variant is extremely rare in gnomAD v4.1, with an allele frequency of 6.20e-07 and zero homozygotes.

PM2 → VUS
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 · 1 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 · 1
Strength Supporting Moderate Strong Very strong
PM2 supporting Pathogenic
Met at Supporting: gnomAD v4.1 total AF 6.20e-07 is below the VCEP PM2 threshold of 0.00002, with zero homozygotes.
The MSH6 VCEP specifies PM2 at allele frequency <0.00002 (<1 in 50,000 alleles) in gnomAD v4.gnomAD v4.1 reports total AF 6.195364628185191e-07, based on 1 alternate allele among 1,614,110 alleles, with zero homozygotes.The highest observed population AF is 8.47450445335209e-07 in the European non-Finnish population, with zero homozygotes, which remains below 0.00002.
cspec ↗gnomad_v4 ↗
Assessed · not applied · 4 not met · 11 not assessed
Pathogenic
PS1 Not assessed: no validated VCEP-Pathogenic alternate-nucleotide comparator for p.Cys765Ser was identified, but the comparator search had a retrieval failure.
PS2 Not assessed: no proband-level parental testing or de novo evidence is documented for assigning the VCEP's 0.5–2 points per proband.
PS3 Not assessed: no variant-specific calibrated functional assay result, functional-odds estimate, or demonstrated MMR defect is available for p.Cys765Ser.
PM3 Not assessed: no affected-proband observation or confirmed phase with a pathogenic MSH6 variant is documented to assign any PM3 points.
PM5 Not assessed: zero same-residue comparator candidates were collected, but the search recorded an HTTP 429 retrieval failure.
PP1 Not assessed: no informative affected-relative meioses or combined Bayes likelihood ratio is documented against the VCEP's 2.08 supporting threshold.
PP3 Not met: governing MSH6 HCI prior probability is 0.4345, below the PP3 supporting threshold of >0.68.
PP4 Not assessed: no patient-specific MSI, tumor-genome, MMR-protein-loss, or qualifying-tumor-count evidence is available for PP4.
Benign
BA1 Not met: gnomAD v4.1 maximum observed population frequency 8.47e-07 is far below the VCEP BA1 threshold of 0.0022.
BS1 Not met: gnomAD v4.1 maximum observed population frequency 8.47e-07 is below the VCEP BS1 lower threshold of 0.00022.
BS2 Not assessed: no qualifying VCEP-defined in-trans co-occurrence and confirmed phase evidence are available for BS2.
BS3 Not assessed: no variant-specific proficient functional assay result or calibrated functional odds value <=0.48 is available for p.Cys765Ser.
BS4 Not assessed: no informative non-segregation data or combined Bayes likelihood ratio is documented against the VCEP's 0.48 upper threshold.
BP4 Not met: governing MSH6 HCI prior probability is 0.4345, above the BP4 supporting threshold of <0.11.
BP5 Not assessed: no qualifying MSS, MMR-expression, BRAF V600E, MLH1-methylation, or tumor-count evidence is available for BP5.
N/A · 12 PVS1 · PS4 · PM1 · PM4 · PM6 · PP2 · PP5 · BP1 · BP2 · BP3 · BP6 · BP7
Research & evidence
Population frequency
gnomAD v4.1 screenshot
gnomAD v4.1
gnomAD v2.1 screenshot
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 6.19536e-07; MAF= 0.00006%, 1/1614110 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.4745e-07; MAF= 0.00008%, 1/1180010 alleles, homozygotes = 0).
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
6.2e-05% · 1 / 1,614,110
0 hom
European (non-Finnish)
1 / 1,180,010
8.5e-05%
+ 9 not observed (Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American)
gnomAD v2.1
Absent · 0 / ?
0 hom
Not observed in any ancestry group.
gnomAD Canada 🇨🇦
Absent · 0 / ?
0 hom
Not observed in any ancestry group.
gnomAD v4 ↗ gnomAD v2 ↗ gnomAD 🇨🇦 ↗
ClinVar screenshot
ClinVar
This variant has been reported in ClinVar as Uncertain significance (4 clinical laboratories) and as Uncertain Significance (1 clinical laboratory). (ClinVarID = 455186)
ClinVar ↗
SpliceAI screenshot
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.921. BayesDel score = 0.498216. HCI prior probability for pathogenicity = 0.4345. MAPP score = 14.04. Custom PP2 score = 0.69.
SpliceAI ↗
Functional / OncoKB screenshot
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.
OncoKB ↗
COSMIC screenshot
COSMIC
Cancer hotspots screenshot
Cancer hotspots
Somatic evidence Not in COSMIC / hotspots
COSMIC
This variant does not lie in a statistically significant hotspot. COSMIC could not be reviewed because the browser session was redirected to the login page before search results were available.
Hotspots
This variant does not lie in a statistically significant hotspot.
COSMIC ↗ Hotspots ↗
Sources & reference links
9Sources
CSpec VCEP
ClinVar
gnomAD v2.1
gnomAD v4.1
gnomAD-Canada
SpliceAI
OncoKB
COSMIC
Cancer hotspots
Triaged references · 7 PMIDs not cited in assessment
24493721 ↗ American Society of Clinical Oncology Expert Statement: collection and use of a cancer family history for oncology providers. CLINVAR
25711197 ↗ Lynch Syndrome: A Primer for Urologists and Panel Recommendations. CLINVAR
25741868 ↗ Standards and guidelines for the interpretation of sequence variants: a joint co CLINVAR
26324357 ↗ American Society of Clinical Oncology Policy Statement Update: Genetic and Genom CLINVAR
26389258 ↗ Cancer Genetics Risk Assessment and Counseling (PDQ®): Health Professional Versi CLINVAR
28492532 ↗ Sherloc: a comprehensive refinement of the ACMG-AMP variant classification crite CLINVAR
34043773 ↗ European guidelines from the EHTG and ESCP for Lynch syndrome: an updated third CLINVAR