Classification rationale

BA1BP7BP4 Benign

MSH6 c.4002-28_4002-26dup

The MSH6 c.4002-28_4002-26dup (p.?) variant has been reported in ClinVar with benign and likely benign interpretations, and no expert panel assertion was identified.¹ This variant is common in population databases, including gnomAD v4.1 with an overall allele frequency of 0.00134155 and an East Asian allele frequency of 0.0283305 (1159/40910 alleles; 5 homozygotes), which is above the MSH6 BA1 threshold of 0.0022; similarly high frequencies are present in gnomAD v2.1 and gnomAD-Canada.² For this intronic duplication, SpliceAI predicts no significant splice impact with a maximum delta score of 0.05, which is below the MSH6 BP4 no-impact threshold of 0.1 and below the PP3 splice-defect threshold of 0.2.³

BA1 + BP7 + BP4 → Benign

1 clinvar ↗

2 gnomad_v4 ↗gnomad_v2 ↗gnomad_canada ↗cspec ↗

3 spliceai ↗cspec ↗

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

v4.1

This variant is present in gnomAD v4.1 (AF= 0.00134155; MAF= 0.13415%, 1883/1403604 alleles, homozygotes = 6) and has highest observed frequency in the East Asian population (AF= 0.0283305; MAF= 2.83305%, 1159/40910 alleles, homozygotes = 5); grpmax FAF= 0.0269749.

v2.1

This variant is present in gnomAD v2.1 (AF= 0.00252012; MAF= 0.25201%, 570/226180 alleles, homozygotes = 2) and has highest observed frequency in the East Asian population (AF= 0.0313601; MAF= 3.13601%, 445/14190 alleles, homozygotes = 2); grpmax FAF= 0.0565538.

🇨🇦 CA

This variant is present in gnomAD-Canada v1.0 (AF= 0.00418751; MAF= 0.41875%, 77/18388 alleles, homozygotes = 3) and has highest observed frequency in the eas population (AF= 0.0470852; grpmax FAF95= 0.0377698).

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

0.13% · 1883 / 1,403,604
6 hom · FAF 2.7%

East Asian 1159 / 40,910	2.8% 5 hom
African/African American 143 / 59,072	0.24% 1 hom
Remaining individuals 127 / 55,562	0.23%
Admixed American 83 / 55,138	0.15%
South Asian 81 / 83,322	0.097%
Middle Eastern 4 / 5,610	0.071%
European (non-Finnish) 283 / 1,016,204	0.028%
European (Finnish) 3 / 58,906	0.0051%

+ 2 not observed (Amish, Ashkenazi Jewish)

gnomAD v2.1

0.25% · 570 / 226,180
2 hom · FAF 5.7%

East Asian 445 / 14,190	3.1% 2 hom
African/African American 57 / 18,028	0.32%
Remaining individuals 12 / 5,958	0.2%
Admixed American 27 / 30,310	0.089%
South Asian 12 / 25,840	0.046%
European (non-Finnish) 16 / 102,806	0.016%
European (Finnish) 1 / 20,050	0.005%

+ 1 not observed (Ashkenazi Jewish)

gnomAD Canada 🇨🇦

0.42% · 77 / 18,388
3 hom · FAF 3.8%

⚠ LCR indel · split

East Asian 63 / 1,338	4.7% 3 hom
Remaining individuals 9 / 1,138	0.79%
Latino/Admixed American 1 / 832	0.12%
South Asian 1 / 1,362	0.073%
European (non-Finnish) 3 / 11,722	0.026%

+ 4 not observed (African/African American, Ashkenazi Jewish, European (Finnish), Middle Eastern)

gnomAD v4 ↗ gnomAD v2 ↗ gnomAD 🇨🇦 ↗

ClinVar

This variant has been reported in ClinVar as Benign (2 clinical laboratories) and as Likely benign (1 clinical laboratory). (ClinVarID = 926536)

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.05).

SpliceAI ↗

Functional No data

No calibrated functional assay or RNA evidence was identified for this variant.

OncoKB ↗

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.

COSMIC ↗

Sources & reference links

8Sources

CSpec VCEP

ClinVar

gnomAD v2.1

gnomAD v4.1

gnomAD-Canada

SpliceAI

OncoKB

COSMIC

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