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NM_000179.3:c.242C>T
p.Ala81Val · 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
BP4
MSH6
c.242C>T
p.Ala81Val
missense · exon 1
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, and inherited pathogenic variants can cause Lynch syndrome through impaired repair and microsatellite instability.

Transcript
NM_000179.3
HGVS · transcript:coding
NM_000179.3:c.242C>T
GRCh38
chr2:47783475 C>T
GRCh37
chr2:48010614 C>T
VUS: BP4 (supporting) is the only met criterion, and it does not satisfy an InSiGHT MSH6 pathogenic or benign combination rule.
Classification rationale
BP4 VUS
MSH6 c.242C>T missense · exon 1

VUS: BP4 Supporting - the exact MSH6 HCI prior is 0.0035, below the VCEP missense threshold of <0.11.

BP4 → 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 · 16 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
BP4 supporting Benign
Met, supporting: exact HCI prior 0.0035 is below the MSH6 VCEP BP4 threshold of <0.11 for missense variants.
The exact HCI-PRIORS-MSH6 table entry for c.242C>T / p.A81V assigns HCI prior probability 0.0035.The MSH6 InSiGHT VCEP specifies BP4_Supporting for a missense variant with HCI prior probability <0.11.REVEL score is 0.216, which is also below the supplied generic BP4_Supporting cutoff of <=0.29 from the ClinGen SVI REVEL calibration (Pejaver et al. 2022, PMID:36413997), although the exact VCEP HCI assignment is governing.
cspec ↗spliceai ↗
Assessed · not applied · 6 not met · 10 not assessed
Pathogenic
PVS1 Not met: NM_000179.3:c.242C>T is a missense variant producing p.(Ala81Val), outside the MSH6 VCEP PVS1 null-variant categories.
PS1 Not met: no documented VCEP-Pathogenic alternate nucleotide change producing the same p.Ala81Val substitution was identified.
PS2 Not assessed: no documented de novo observation with maternity and paternity confirmation or variant-specific tumor evidence is available for this variant.
PS3 Not assessed: no variant-specific functional assay result or calibrated pathogenicity odds are available for MSH6 c.242C>T.
PM2 Not met: gnomAD v4.1 total AF is 0.000113943645, exceeding the MSH6 PM2 threshold of <0.00002.
PM3 Not assessed: no qualifying affected-proband biallelic observation or documented cis/trans phase was available to assign the MSH6 PM3 point thresholds.
PM5 Not assessed: 0 same-residue candidates were available, but comparator harvesting ended with an HTTP 429 failure, leaving PM5 evidence incomplete.
PP1 Not assessed: no pedigree segregation data or combined Bayes likelihood ratio is reported, so the VCEP thresholds >2.08, >4.3, and >18.7 cannot be evaluated.
PP3 Not met: HCI prior 0.0035 is below the MSH6 VCEP PP3 threshold of >0.68, and REVEL 0.216 is below the generic 0.644 threshold.
PP4 Not assessed: exact-variant cancer observations lack the required MSI-H, tumor-genome, or MSH6-consistent IHC findings and qualifying tumor count.
Benign
BA1 Not met: gnomAD v4.1 grpmax FAF is 0.00012624, below the MSH6 BA1 threshold of 0.0022.
BS1 Not met: gnomAD v4.1 grpmax FAF is 0.00012624, below the MSH6 BS1 lower boundary of 0.00022.
BS2 Not assessed: no documented MSH6 pathogenic-variant co-occurrence in trans with qualifying cancer age, CMMRD assessment, and confirmed phase.
BS3 Not assessed: no variant-specific proficient-function assay result or calibrated benign functional odds are available for MSH6 c.242C>T.
BS4 Not assessed: no non-segregation observations or combined Bayes likelihood ratio is reported, so the BS4 thresholds <0.05 and 0.05-0.48 cannot be evaluated.
BP5 Not assessed: no variant-specific MSS, MMR-IHC inconsistency, BRAF V600E, MLH1 methylation, or qualifying tumor count is documented.
N/A · 11 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= 0.000113944; MAF= 0.01139%, 164/1439308 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 0.000145039; MAF= 0.01450%, 159/1096258 alleles, homozygotes = 0); grpmax FAF= 0.00012624.
v2.1
This variant is present in gnomAD v2.1 (AF= 3.4827e-05; MAF= 0.00348%, 3/86140 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.0047e-05; MAF= 0.00800%, 3/37478 alleles, homozygotes = 0); grpmax FAF= 1.591e-05.
🇨🇦 CA
Not available in gnomAD-Canada v1.0.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.011% · 164 / 1,439,308
0 hom · FAF 0.013%
European (non-Finnish)
159 / 1,096,258
0.015%
African/African American
3 / 66,738
0.0045%
Remaining individuals
2 / 55,154
0.0036%
+ 7 not observed (Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish)
gnomAD v2.1
0.0035% · 3 / 86,140
0 hom · FAF 0.0016%
European (non-Finnish)
3 / 37,478
0.008%
+ 7 not observed (African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals, South Asian)
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 (7 clinical laboratories) and as Likely benign (5 clinical laboratories). (ClinVarID = 127571)
ClinVar ↗
SpliceAI screenshot
In silico
SpliceAI predicts possible splice impact for this variant (max delta score = 0.32). REVEL score = 0.216. BayesDel score = -0.293941. HCI prior probability for pathogenicity = 0.0035. MAPP score = 4.76. Custom PP2 score = 0.003.
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. This variant has not previously been reported in somatic cancers (COSMIC).
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 · 8 PMIDs not cited in assessment
23047549 ↗ Frequency of mutations in mismatch repair genes in a population-based study of women with ovarian cancer. CLINVAR
23621914 ↗ CoDP: predicting the impact of unclassified genetic variants in MSH6 by the combination of different properties of the protein. CLINVAR
23788249 ↗ ACMG recommendations for reporting of incidental findings in clinical exome and CLINVAR
24905773 ↗ Endometrial cancer: a review and current management strategies: part I. CLINVAR
24929052 ↗ Endometrial cancer: a review and current management strategies: part II. CLINVAR
25741868 ↗ Standards and guidelines for the interpretation of sequence variants: a joint co CLINVAR
26467025 ↗ A Standardized DNA Variant Scoring System for Pathogenicity Assessments in Mende CLINVAR
27363726 ↗ Classification of genetic variants in genes associated with Lynch syndrome using a clinical history weighting algorithm. CLINVAR