NM_000179.3:c.3603C>A (p.Leu1201=) is a synonymous variant in MSH6 exon 7. SpliceAI predicts no splicing impact (delta = 0.00). The variant is extremely rare in gnomAD v4.1 (1/1,613,414 alleles; AF = 6.2 × 10⁻⁷) and absent from gnomAD v2.1, gnomAD-Canada, ClinVar, and COSMIC.1 Under the InSiGHT MSH6 VCEP v2.0.0: BP7_Supporting is met because this is a synonymous variant. BP4_Supporting is met because SpliceAI delta (0.00) ≤ 0.1. PM2_Supporting is met because the variant allele frequency (6.2 × 10⁻⁷) is below the VCEP threshold of <0.00002.2 Per the InSiGHT VCEP combining rules, two Benign Supporting criteria (BP4_Supporting + BP7_Supporting) with one Pathogenic Supporting criterion (PM2_Supporting) results in Uncertain Significance (VUS) — Rule31 (≥1 Benign.Supporting + ≥1 Pathogenic.Supporting → VUS Conflicting) takes precedence over Rule19 (≥2 Benign.Supporting → Likely Benign).3 PVS1, PS1, PM5, PS4, PP2, PP5, PM1, PM6, BP1, BP2, BP3, BP6 are not applicable. PS2, PS3, PP1, PP4, BS2, BS3, BS4, BP5 are not assessed due to absence of de novo, functional, tumor phenotype, co-segregation, or co-occurrence data.
MSH6
Final classification
Likely Benign
MSH6 c.3603C>A · p.Leu1201=
MSH6
NM_000179.3:c.3603C>A (p.Leu1201=) is a synonymous variant in MSH6 exon 7. SpliceAI predicts no splicing impact (delta = 0.00). The variant is extremely rare in gnomAD v4.1 (1/1,613,414 alleles; AF = 6.2 × 10⁻⁷) and absent from gnomAD v2.1, gnomAD-Canada, ClinVar, and COSMIC.
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.3603C>A
PM2 + BP4 + BP7
→
Likely Benign
3
cspec ↗final_classification_framework
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
NM_000179.3:c.3603C>A is extremely rare in population databases. In gnomAD v4.1 it is observed in 1 of 1,613,414 alleles (AF = 6.2 × 10⁻⁷), which is below the InSiGHT MSH6 VCEP PM2_Supporting threshold of <0.00002 (<1 in 50,000 alleles). The variant is absent from gnomAD v2.1 and gnomAD-Canada.
gnomAD v4.1: 1/1613414 alleles (AF = 6.2 × 10⁻⁷)
✓
BP4
supporting
Benign
SpliceAI predicts no splicing impact for this synonymous variant (max delta score = 0.00). Under the InSiGHT MSH6 VCEP v2.0.0 BP4 rule, synonymous variants with SpliceAI delta ≤0.1 meet BP4_Supporting.
Synonymous variant (p.Leu1201=)SpliceAI max delta = 0.00 (≤0.1 threshold for BP4_Supporting)
✓
BP7
supporting
Benign
NM_000179.3:c.3603C>A is a synonymous (silent) variant (p.Leu1201=). Under the InSiGHT MSH6 VCEP v2.0.0, synonymous variants meet BP7_Supporting. SpliceAI predicts no splicing impact (max delta = 0.00), supporting that this variant does not alter splicing.
Synonymous variant (p.Leu1201=)no amino acid changeSpliceAI max delta = 0.00
Assessed · not applied
Pathogenic
PS2
No de novo observations have been reported for NM_000179.3:c.3603C>A.
PS3
No calibrated functional assay data are available for NM_000179.3:c.3603C>A.
PP1
No co-segregation data are available for NM_000179.3:c.3603C>A.
PP3
PP3 is not met for this synonymous variant.
PP4
No tumor phenotype data (MSI-H status, MMR IHC) are available for NM_000179.3:c.3603C>A.
Benign
BA1
The gnomAD v4.1 allele frequency of 6.2 × 10⁻⁷ (1/1,613,414) is well below the InSiGHT MSH6 VCEP BA1 Stand Alone threshold of ≥0.0022 (0.22%).
BS1
The gnomAD v4.1 allele frequency of 6.2 × 10⁻⁷ (1/1,613,414) is below the InSiGHT MSH6 VCEP BS1 Strong threshold of ≥0.00022 (0.022%).
BS2
No data are available regarding 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 are available for NM_000179.3:c.3603C>A to assess normal protein function.
BS4
No co-segregation data are available to assess lack of segregation with disease.
BP5
No tumor phenotype data (MSS status, MMR IHC, BRAF V600E, MLH1 methylation) are available for NM_000179.3:c.3603C>A.
N/A · 12
PVS1 · PS1 · PS4 · PM1 · PM5 · PM6 · PP2 · PP5 · BP1 · BP2 · BP3 · BP6
Research & evidence
Population frequency · supports benign
gnomAD v4.1
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 6.19804e-07; MAF= 0.00006%, 1/1613414 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.47749e-07; MAF= 0.00008%, 1/1179594 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 / 1,613,414
0 hom
0 hom
European (non-Finnish) 1 / 1,179,594 |
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
0 hom
Not observed in any ancestry group.
gnomAD Canada 🇨🇦
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
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