NM_000179.3:c.260+21T>G in MSH6 is an intronic variant located at position +21 of intron 1. SpliceAI predicts no splicing impact (max delta score = 0.00).1 The variant is present at extremely low frequency in gnomAD v4.1 (6/1,388,350 alleles, AF = 4.32e-06, grpmax FAF = 1.10e-05), meeting the InSiGHT MSH6 VCEP v2.0.0 PM2_Supporting criterion (AF < 0.00002).2 The variant is absent from gnomAD v2.1 (0/34,192 alleles).3 SpliceAI predicts no splicing impact (max delta = 0.00), meeting the VCEP BP4_Supporting criterion (delta ≤ 0.1 for intronic variants).4 The variant is intronic at position +21, meeting the VCEP BP7_Supporting criterion (intronic variant at or beyond +7 from the exon boundary).5 The gnomAD v4.1 grpmax FAF (1.10e-05) does not meet VCEP BA1 (≥0.0022) or BS1 (≥0.00022) frequency thresholds.6 This variant has been reported in ClinVar as Likely benign by one clinical laboratory (ClinVar Variation ID: 491905).7
MSH6
Final classification
Likely Benign
MSH6 c.260+21T>G · p.?
MSH6
NM_000179.3:c.260+21T>G in MSH6 is an intronic variant located at position +21 of intron 1. SpliceAI predicts no splicing impact (max delta score = 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 benign, BP7 supporting benign; maps to Likely Benign.
Classification rationale
PM2
BP4BP7
Likely Benign
MSH6 c.260+21T>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
NM_000179.3:c.260+21T>G has an allele frequency of 4.32e-06 (6/1,388,350 alleles, grpmax FAF = 1.10e-05) in gnomAD v4.1, which is below the InSiGHT MSH6 VCEP v2.0.0 PM2_Supporting threshold of <0.00002 (1 in 50,000 alleles).
gnomAD v4.1: AC=6AN=1388
✓
BP4
supporting
Benign
Under the InSiGHT MSH6 VCEP v2.0.0, BP4_Supporting is met for intronic variants when SpliceAI predicts no splicing impact with delta score ≤ 0.1. SpliceAI predicts no significant splice impact for NM_000179.3:c.260+21T>G (max delta score = 0.00).
SpliceAI max delta score = 0.00meeting the VCEP BP4_Supporting threshold of ≤ 0.1 for intronic variants.
✓
BP7
supporting
Benign
Under the InSiGHT MSH6 VCEP v2.0.0, BP7_Supporting applies to intronic variants at or beyond -21/+7 from the exon boundary. NM_000179.3:c.260+21T>G is located at position +21 in intron 1, which is beyond the +7 threshold, satisfying the VCEP BP7 rule.
Variant is intronic at position +21beyond the VCEP BP7 threshold of +7 from the exon boundary.
Assessed · not applied
Pathogenic
PS2
No de novo observation data are available for NM_000179.3:c.260+21T>G.
PS3
No calibrated functional assay data are available for NM_000179.3:c.260+21T>G.
PP1
No co-segregation data are available for NM_000179.3:c.260+21T>G.
PP3
Under the InSiGHT MSH6 VCEP v2.0.0, PP3 applies to (a) missense variants with HCI prior >0.68, or (b) intronic/splice variants with SpliceAI delta score ≥ 0.2.
PP4
No tumor phenotype data (MSI status, MMR IHC) are available for carriers of NM_000179.3:c.260+21T>G.
Benign
BA1
Under the InSiGHT MSH6 VCEP v2.0.0, BA1 requires gnomAD v4 grpmax filtering allele frequency ≥ 0.0022 (0.22%).
BS1
Under the InSiGHT MSH6 VCEP v2.0.0, BS1 requires gnomAD v4 grpmax filtering allele frequency ≥ 0.00022 (0.022%) and < 0.0022.
BS2
No data are available demonstrating 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.260+21T>G.
BS4
No co-segregation data are available for NM_000179.3:c.260+21T>G.
BP5
No tumor data are available for NM_000179.3:c.260+21T>G.
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= 4.32168e-06; MAF= 0.00043%, 6/1388350 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 6.66933e-05; MAF= 0.00667%, 2/29988 alleles, homozygotes = 0); grpmax FAF= 1.104e-05.
v2.1
This variant is present in gnomAD v2.1 (AF= 0; MAF= 0.00000%, 0/34192 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0; MAF= 0.00000%, 0/852 alleles, homozygotes = 0).
🇨🇦 CA
This variant is absent from gnomAD-Canada.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.00043%
· 6 / 1,388,350
0 hom · FAF 0.0011%
0 hom · FAF 0.0011%
Admixed American 2 / 29,988 |
0.0067% |
African/African American 1 / 62,352 |
0.0016% |
European (non-Finnish) 3 / 1,069,618 |
0.00028% |
+ 7 not observed (Remaining individuals, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish)
gnomAD v2.1
Absent
· 0 / 34,192
0 hom
0 hom
Not observed in any ancestry group.
+ 8 not observed (African/African American, Admixed American, Ashkenazi Jewish, East Asian, 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 (1 clinical laboratory). (ClinVarID = 491905)
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 · 2 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
25394175 ↗
A practice guideline from the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors: referral indications for cancer predisposition assessment.
CLINVAR