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 met · select any tile
Met
Not met
Not assessed
N/A
Strength
very strong
supporting
Pathogenic evidence
PVS
PS
PM
PP
Benign evidence
BA
BS
BP
—
—
—
Rationale
Select a criterion.
Sources
Evidence used
Gaps remaining
Rule
—
Research & evidence
Population frequency · supports benign
gnomAD v4.1
gnomAD v2.1
Population frequency
Overall AF
6 / 1,388,350
0.00043%
Highest · Admixed American
0.0067%
Homozygotes
0
grpmax FAF
0.0011%
Allele frequency by ancestry — gnomAD v4.1
observed in 3 of 9 groups
| Ancestry | Allele count | Frequency | Homozygotes |
|---|---|---|---|
| Admixed American | 2 / 29,988 | 0.0067% | 0 |
| African/African American | 1 / 62,352 | 0.0016% | 0 |
| European (non-Finnish) | 3 / 1,069,618 | 0.00028% | 0 |
| European (Finnish) | 0 / 51,428 | — | — |
| Amish | 0 / 816 | — | — |
| East Asian | 0 / 34,478 | — | — |
| Middle Eastern | 0 / 4,342 | — | — |
| South Asian | 0 / 61,698 | — | — |
| Ashkenazi Jewish | 0 / 20,610 | — | — |
“
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.
Overall AF
Not observed
Homozygotes
0
Not observed in any ancestry group across 8 populations in gnomAD 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).
“
This variant is absent from gnomAD-Canada.
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.
Literature · 2 PMIDs triaged · 2 high-priority
2papers screened
Papers triaged by theme: functional/splicing/segregation/case_observation. high_priority_papers include abstract snippets. Use these to support PS3/BS3/PS4/PP1/PP3/PP5.
25741868 ↗
functional
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.
The American College of Medical Genetics and Genomics (ACMG) previously developed guidance for the interpretation of sequence variants.(1) In the past decade, sequencing technology has evolved rapidly with the advent of high-throughput next-generation sequencing. By adopting and leveraging next-generation sequencing, clinical laboratories are now performing an ever-increasing catalogue of genetic
BS3PP5PS3PS4
25394175 ↗
case observation
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.
The practice guidelines of the American College of Medical Genetics and Genomics (ACMG) and the National Society of Genetic Counselors (NSGC) are developed by members of the ACMG and NSGC to assist medical geneticists, genetic counselors, and other health-care providers in making decisions about appropriate management of genetic concerns, including access to and/or delivery of services. Each pract
PP5PS4
Sources & reference links