NM_000179.3:c.3162C>T (p.Ile1054=) is a synonymous variant in exon 4 of MSH6 with a gnomAD v4.1 grpmax filtering allele frequency of 0.059% (79/1,610,432 alleles), meeting VCEP BS1 at Strong strength.1 SpliceAI predicts no splicing impact for this synonymous variant (max delta score 0.03), meeting VCEP BP4 at Supporting strength.2 The variant is synonymous and located beyond the splice consensus region in exon 4, meeting VCEP BP7 at Supporting strength.3 ClinVar classifies this variant as Benign/Likely benign (Variation ID 184018, review status: criteria provided, multiple submitters, no conflicts).4 No pathogenic criteria are met for this variant. Under VCEP InSiGHT MMR v2.0.0 classification rules, one Benign Strong criterion (BS1) plus one or more Benign Supporting criteria (BP4, BP7) yields a classification of Likely Benign (Rule 18).5
MSH6
Final classification
Likely Benign
MSH6 c.3162C>T · p.Ile1054=
MSH6
NM_000179.3:c.3162C>T (p.Ile1054=) is a synonymous variant in exon 4 of MSH6 with a gnomAD v4.1 grpmax filtering allele frequency of 0.059% (79/1,610,432 alleles), meeting VCEP BS1 at Strong strength.
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: BS1 strong benign, BP4 supporting benign, BP7 supporting benign; maps to Likely Benign.
Classification rationale
BS1BP4BP7
Likely Benign
MSH6 c.3162C>T
BS1 + 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
✓
BS1
strong
Benign
gnomAD v4.1 grpmax filtering allele frequency is 0.00058972 (0.059%), which falls within the VCEP BS1 range of ≥ 0.00022 (0.022%) and < 0.0022 (0.22%). This allele frequency is inconsistent with a fully penetrant dominant disorder, meeting BS1 at Strong strength.
gnomAD v4.1 grpmax FAF = 0.00058972 (79/1610432 alleles)
✓
BP4
supporting
Benign
Synonymous variant with SpliceAI max delta score of 0.03, which is ≤ 0.1. Under VCEP BP4 rules, synonymous variants with SpliceAI delta ≤ 0.1 meet BP4_Supporting as they are predicted to have no splicing impact.
SpliceAI max delta = 0.03 (<= 0.1 threshold for no splicing impact)
✓
BP7
supporting
Benign
NM_000179.3:c.3162C>T is a synonymous variant in exon 4, located 10 bases upstream of the 3' exon boundary (c.3172), which satisfies the VCEP BP7 requirement of being at or beyond +7 from the 3' splice site. SpliceAI predicts no splicing impact (delta 0.03), supporting no effect on splicing.
Synonymous variant c.3162C>T at position -10 from 3' exon boundarySpliceAI delta 0.03
Assessed · not applied
Pathogenic
PS2
No de novo observations identified in ClinVar submissions, published literature, or other evidence sources for NM_000179.3:c.3162C>T.
PS3
No calibrated functional assay data identified for this variant in the VCEP MMR functional assay documentation spreadsheet or in the published literature.
PM2
PM2_Supporting threshold under the VCEP requires absence or extreme rarity with gnomAD v4 allele frequency below 0.00002 (<1 in 50,000 alleles).
PP1
No co-segregation data available in published literature or ClinVar submissions for NM_000179.3:c.3162C>T.
PP3
Synonymous variant; VCEP PP3 rules for missense variants require HCI prior >0.68, which is not applicable (synonymous changes are not in the HCI missense prior table).
PP4
No tumor MSI or immunohistochemistry data available for this variant.
Benign
BA1
VCEP BA1 threshold requires gnomAD v4 grpmax filtering allele frequency ≥ 0.0022 (0.22%).
BS2
No evidence of co-occurrence in trans with a known pathogenic MSH6 variant in a patient with colorectal cancer after age 45 without CMMRD features.
BS3
No calibrated functional assay data identified for this variant in the VCEP MMR functional assay documentation.
BS4
No segregation or lack-of-segregation data available for NM_000179.3:c.3162C>T.
BP5
No tumor data available to assess MSS status or MMR protein expression.
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= 4.90552e-05; MAF= 0.00491%, 79/1610432 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0.000746607; MAF= 0.07466%, 56/75006 alleles, homozygotes = 0); grpmax FAF= 0.00058972.
v2.1
This variant is present in gnomAD v2.1 (AF= 0.000104609; MAF= 0.01046%, 29/277224 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0.000895547; MAF= 0.08955%, 22/24566 alleles, homozygotes = 0); grpmax FAF= 0.00063248.
🇨🇦 CA
Absent from gnomAD-Canada v1.0.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.0049%
· 79 / 1,610,432
0 hom · FAF 0.059%
0 hom · FAF 0.059%
African/African American 56 / 75,006 |
0.075% |
Middle Eastern 1 / 6,062 |
0.016% |
East Asian 3 / 44,866 |
0.0067% |
Remaining individuals 4 / 62,488 |
0.0064% |
European (Finnish) 2 / 60,486 |
0.0033% |
Admixed American 1 / 59,990 |
0.0017% |
European (non-Finnish) 12 / 1,179,956 |
0.001% |
+ 3 not observed (Amish, South Asian, Ashkenazi Jewish)
gnomAD v2.1
0.01%
· 29 / 277,224
0 hom · FAF 0.063%
0 hom · FAF 0.063%
African/African American 22 / 24,566 |
0.09% |
East Asian 3 / 19,868 |
0.015% |
European (Finnish) 2 / 21,538 |
0.0093% |
Admixed American 1 / 35,368 |
0.0028% |
European (non-Finnish) 1 / 127,836 |
0.00078% |
+ 3 not observed (Ashkenazi Jewish, Remaining individuals, South Asian)
gnomAD Canada 🇨🇦
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
ClinVar
This variant is present in ClinVar (Variation ID: 184018); submission details unavailable.
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.03).
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 previously been reported in somatic cancers (COSMIC; COSV52282023, n = 1 times).
Hotspots
This variant does not lie in a statistically significant hotspot.
Sources & reference links
9Sources
Triaged references · 8 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
26467025 ↗
A Standardized DNA Variant Scoring System for Pathogenicity Assessments in Mendelian Disorders.
CLINVAR
23788249 ↗
ACMG recommendations for reporting of incidental findings in clinical exome and genome sequencing.
CLINVAR
24493721 ↗
American Society of Clinical Oncology Expert Statement: collection and use of a cancer family history for oncology providers.
CLINVAR
26324357 ↗
American Society of Clinical Oncology Policy Statement Update: Genetic and Genomic Testing for Cancer Susceptibility.
CLINVAR
28492532 ↗
Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.
CLINVAR