The MSH6 NM_000179.3:c.-2G>T (NP_000170.1:p.?) variant has not been observed in COSMIC and has been reported in ClinVar with mixed single-submitter interpretations, including uncertain significance and likely benign.1 This variant is present at very low frequency in population databases, with gnomAD v4.1 total allele frequency 1.24133e-05 (20/1611176 alleles) and gnomAD v2.1 total allele frequency 1.45244e-05 (4/275398 alleles), which supports PM2_Supporting under the MSH6 VCEP threshold of less than 0.00002.2 Available evidence does not show a qualifying constitutional RNA or other calibrated functional study for this variant, so PS3 and BS3 are not currently supported.3 SpliceAI predicts no significant splice impact for this variant with a max delta score of 0.00, but this 5′ UTR substitution does not fit the MSH6 VCEP PP3 or BP4 rule types for missense or qualifying intronic/non-canonical splice variants.4
Final classification
VUS
PM2
MSH6
c.-2G>T
p.?
This variant
The MSH6 NM_000179.3:c.-2G>T (NP_000170.1:p.?) variant has not been observed in COSMIC and has been reported in ClinVar with mixed single-submitter interpretations, including uncertain significance and likely benign.
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; no rule matched the adjudicated criteria.
Classification rationale
PM2
VUS
MSH6 c.-2G>T
PM2
→
VUS
3
cspec ↗PMID:26888055 ↗vcep_functional_assay_svi_documentation_mmrvcep_functional_assay_flowchart
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 · 12 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
This variant is present at very low frequency in gnomAD v4.1 with a total allele frequency of 1.24133e-05 (20/1611176 alleles), which is below the MSH6 VCEP PM2 threshold of 0.00002, so PM2_Supporting is met.
gnomAD v4.1 total AF 1.24133e-05gnomAD v2.1 total AF 1.45244e-05MSH6 VCEP PM2 threshold <0.00002
Assessed · not applied
· 3 not met · 9 not assessed
Pathogenic
PVS1
Although the generic scaffold flagged canonical splice review, this variant is annotated as NM_000179.3:c.-2G>T, a 5′ UTR substitution immediately upstream of the coding start.
PS2
No de novo data were identified, so PS2 was not assessed.
PS3
No variant-specific calibrated functional assay or constitutional RNA study demonstrating an abnormal effect was identified, so PS3 was not assessed.
PM3
No qualifying in trans observations for constitutional mismatch repair deficiency scoring were identified, so PM3 was not assessed.
PP1
No segregation data were identified to calculate the Bayes likelihood ratio required for PP1, so this criterion was not assessed.
PP4
No tumor microsatellite instability or mismatch repair immunohistochemistry evidence was identified for this variant, so PP4 was not assessed.
Benign
BA1
The gnomAD v4.1 filtering allele frequency is 2.987e-05, which is below the MSH6 VCEP BA1 threshold of 0.0022, so BA1 is not met.
BS1
The gnomAD v4.1 filtering allele frequency is 2.987e-05, which is below the MSH6 VCEP BS1 threshold of 0.00022, so BS1 is not met.
BS2
No confirmed in trans observation with a pathogenic MSH6 variant in an older individual without features of constitutional mismatch repair deficiency was identified, so BS2 was not assessed.
BS3
No variant-specific RNA or other calibrated functional assay showing no damaging effect was identified, so BS3 was not assessed.
BS4
No segregation data showing lack of co-segregation with disease were identified, so BS4 was not assessed.
BP5
No qualifying evidence for an alternate molecular explanation with mismatch repair findings inconsistent with MSH6 was identified, so BP5 was not assessed.
N/A · 15
PS1 · PS4 · PM1 · PM4 · PM5 · PM6 · PP2 · PP3 · PP5 · BP1 · BP2 · BP3 · BP4 · BP6 · BP7
Research & evidence
Population frequency
gnomAD v4.1
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 1.24133e-05; MAF= 0.00124%, 20/1611176 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 0.0002404; MAF= 0.02404%, 15/62396 alleles, homozygotes = 0); grpmax FAF= 2.987e-05.
v2.1
This variant is present in gnomAD v2.1 (AF= 1.45244e-05; MAF= 0.00145%, 4/275398 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 0.000141084; MAF= 0.01411%, 1/7088 alleles, homozygotes = 0).
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.0012%
· 20 / 1,611,176
0 hom · FAF 0.003%
0 hom · FAF 0.003%
Remaining individuals 15 / 62,396 |
0.024% |
East Asian 4 / 44,672 |
0.009% |
European (non-Finnish) 1 / 1,179,344 |
8.5e-05% |
+ 7 not observed (Admixed American, European (Finnish), Amish, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American)
gnomAD v2.1
0.0015%
· 4 / 275,398
0 hom
0 hom
Remaining individuals 1 / 7,088 |
0.014% |
East Asian 2 / 19,398 |
0.01% |
South Asian 1 / 30,236 |
0.0033% |
+ 5 not observed (African/African American, Admixed American, Ashkenazi Jewish, European (Finnish), European (non-Finnish))
ClinVar
This variant has been reported in ClinVar as Uncertain significance (8 clinical laboratories) and as Likely benign (5 clinical laboratories). (ClinVarID = 142219)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).
Functional
No data
No calibrated functional assay or RNA evidence was identified for this variant.
COSMIC
Somatic evidence
COSMIC
This variant has not previously been reported in somatic cancers (COSMIC).
Hotspots
This variant does not lie in a statistically significant cancer hotspot.
Sources & reference links
Triaged references · 9 PMIDs not cited in assessment
25070057 ↗
Guidelines on genetic evaluation and management of Lynch syndrome: a consensus statement by the US Multi-society Task Force on colorectal cancer.
CLINVAR
25645574 ↗
ACG clinical guideline: Genetic testing and management of hereditary gastrointestinal cancer syndromes.
CLINVAR
25741868 ↗
Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.
CLINVAR
26467025 ↗
A Standardized DNA Variant Scoring System for Pathogenicity Assessments in Mendelian Disorders.
CLINVAR
26888055 ↗
Understanding the Pathogenicity of Noncoding Mismatch Repair Gene Promoter Variants in Lynch Syndrome.
CLINVAR
28301460 ↗
Clinical laboratories collaborate to resolve differences in variant interpretations submitted to ClinVar.
CLINVAR
33939675 ↗
Genetic Variants in Patients With a Family History of Pancreatic Cancer: Impact of Multigene Panel Testing.
CLINVAR
34197922 ↗
Use of Treatment-Focused Tumor Sequencing to Screen for Germline Cancer Predisposition.
CLINVAR
28492532 ↗
Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.
CLINVAR