c.2526T>G (p.Ala842=) is a synonymous variant in MSH6 exon 4 with no predicted effect on splicing (SpliceAI max delta = 0.00).1 The variant is extremely rare in population databases, with an overall allele frequency of 8.06×10⁻⁶ in gnomAD v4.1 (13/1,613,006 alleles, 0 homozygotes), meeting PM2_Supporting per VCEP MSH6 (threshold <0.00002).2 As a synonymous variant with no predicted splicing impact (SpliceAI delta = 0.00), BP4_Supporting is met per VCEP MSH6 rule for synonymous variants with SpliceAI delta ≤0.1.3 The variant is a synonymous substitution located deep within exon 4 (c.628-3172), far from splice junctions, meeting BP7_Supporting per VCEP MSH6 rule for synonymous variants at or beyond -21/+7 position.4 This variant has been reported in ClinVar as Likely benign by 5 clinical laboratories, Likely Benign by 1, and Benign by 1 (ClinVar ID: 186376, review status: criteria provided, single submitter). However, BP6 is not applicable per VCEP rules.5 No functional studies, segregation data, tumor phenotype data, or de novo observations have been reported for this variant. No publications mention NM_000179.3:c.2526T>G specifically.6
MSH6
Final classification
Likely Benign
MSH6 c.2526T>G · p.Ala842=
MSH6
c.2526T>G (p.Ala842=) is a synonymous variant in MSH6 exon 4 with no predicted effect on splicing (SpliceAI max delta = 0.00).
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: matched Rule19 (Benign.Supporting >=2) with applied criteria: PM2 supporting, BP4 supporting, BP7 supporting; maps to Likely Benign.
Classification rationale
PM2
BP4BP7
Likely Benign
MSH6 c.2526T>G
PM2 + BP4 + BP7
→
Likely Benign
Gene diagram
· NM_000179.3 · variants mapped to exon structure
MSH6
NM_000179.3
Fetching transcript structure from UCSC…
Applied criteria · 3 applied · 11 assessed
Applied · 3
Strength
Supporting
Moderate
Strong
Very strong
✓
PM2
supporting
Pathogenic
c.2526T>G is extremely rare in population databases. In gnomAD v4.1 the overall allele frequency is 8.06×10⁻⁶ (13/1,613,006 alleles, 0 homozygotes), which is below the VCEP MSH6 PM2_Supporting threshold of <0.00002 (<1 in 50,000 alleles). The variant is also rare in gnomAD v2.1 (AF=3.62×10⁻⁵, 9/248,608 alleles).
gnomAD v4.1 overall AF = 8.06×10⁻⁶below VCEP PM2 threshold of <2×10⁻⁵. gnomAD v2.1 AF = 3.62×10⁻⁵. Highest subpopulation frequency in East Asian (v4: AF=2.67×10⁻⁴v2: AF=4.91×10⁻⁴).
✓
BP4
supporting
Benign
SpliceAI predicts no splicing impact for this synonymous variant (max delta score = 0.00, ≤0.1). Per the VCEP MSH6 BP4_Supporting rule, synonymous variants with SpliceAI delta score ≤0.1 meet BP4_Supporting.
SpliceAI max delta = 0.00well below the BP4_Supporting threshold of ≤0.1 for synonymous variants. REVEL and BayesDel are not applicable (synonymous variant). HCI prior not found.
✓
BP7
supporting
Benign
c.2526T>G is a synonymous (silent) variant located at coding position 2526 in exon 4 (c.628-3172), well within the exon interior and far from canonical splice sites. Per VCEP MSH6 BP7, synonymous variants at or beyond the -21/+7 splice region meet BP7_Supporting. Variants may satisfy both BP7 and BP4 per VCEP rules.
Synonymous variant at c.2526 in exon 4 (spanning c.628-3172)far from exon-intron boundaries. SpliceAI confirms no predicted splice impact (delta=0.00).
Assessed · not applied
Pathogenic
PS2
No de novo observations have been reported for this variant.
PS3
No variant-specific functional data are available for c.2526T>G.
PP1
No co-segregation data are available for this variant.
PP3
VCEP MSH6 PP3 criteria do not apply to this variant.
PP4
No MSI-H tumor data or MMR protein expression data are available for this variant.
Benign
BA1
The gnomAD v4 grpmax filtering allele frequency for c.2526T>G is 0.0001539 (0.015%), which is far below the VCEP MSH6 BA1 stand-alone threshold of ≥0.0022 (0.22%).
BS1
The gnomAD v4 grpmax filtering allele frequency for c.2526T>G is 0.0001539 (0.015%), which falls below the VCEP MSH6 BS1 threshold of ≥0.00022 (0.022%).
BS2
No evidence of co-occurrence in trans with a known pathogenic MSH6 variant in a patient with colorectal cancer after age 45 has been identified.
BS3
No variant-specific functional data demonstrating benign impact are available for c.2526T>G.
BS4
No segregation data demonstrating lack of co-segregation with disease are available for this variant.
BP5
No tumor data (MSS tumors, retained MMR protein expression, or BRAF V600E/MLH1 methylation) are available for this variant.
N/A · 11
PVS1 · PS1 · PS4 · PM1 · PM5 · PM6 · PP2 · PP5 · BP1 · BP2 · BP6
Research & evidence
Population frequency · supports benign
gnomAD v4.1
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 8.05949e-06; MAF= 0.00081%, 13/1613006 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 0.000267284; MAF= 0.02673%, 12/44896 alleles, homozygotes = 0); grpmax FAF= 0.0001539.
v2.1
This variant is present in gnomAD v2.1 (AF= 3.62016e-05; MAF= 0.00362%, 9/248608 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 0.000490838; MAF= 0.04908%, 9/18336 alleles, homozygotes = 0); grpmax FAF= 0.00025523.
🇨🇦 CA
Absent from gnomAD-Canada v1.0.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.00081%
· 13 / 1,613,006
0 hom · FAF 0.015%
0 hom · FAF 0.015%
East Asian 12 / 44,896 |
0.027% |
European (non-Finnish) 1 / 1,179,774 |
8.5e-05% |
+ 8 not observed (Remaining individuals, Admixed American, European (Finnish), Amish, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American)
gnomAD v2.1
0.0036%
· 9 / 248,608
0 hom · FAF 0.026%
0 hom · FAF 0.026%
East Asian 9 / 18,336 |
0.049% |
+ 7 not observed (African/African American, Admixed American, Ashkenazi Jewish, European (Finnish), European (non-Finnish), Remaining individuals, South Asian)
gnomAD Canada 🇨🇦
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
ClinVar
This variant has been reported in ClinVar as Likely benign (5 clinical laboratories) and as Likely Benign (1 clinical laboratory) and as Benign (1 clinical laboratory). (ClinVarID = 186376)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).
Functional
Unknown Oncogenic Effect
OncoKB identified curated literature and non-variant-specific oncogenicity context for review; listed oncogenicity label: Unknown Oncogenic Effect.
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 · 7 PMIDs not cited in assessment
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
31672839 ↗
Management of patients with increased risk for familial pancreatic cancer: updated recommendations from the International Cancer of the Pancreas Screening (CAPS) Consortium.
CLINVAR
15604628 ↗
Genetic cancer risk assessment and counseling: recommendations of the national society of genetic counselors.
CLINVAR
23535968 ↗
Informing family members of individuals with Lynch syndrome: a guideline for clinical geneticists.
CLINVAR
25356965 ↗
ACMG policy statement: updated recommendations regarding analysis and reporting of secondary findings in clinical genome-scale sequencing.
CLINVAR
25452455 ↗
Hereditary colorectal cancer syndromes: American Society of Clinical Oncology Clinical Practice Guideline endorsement of the familial risk-colorectal cancer: European Society for Medical Oncology Clinical Practice Guidelines.
CLINVAR
28492532 ↗
Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.
CLINVAR