Classification rationale

BA1BP4 Benign

MLH1 c.1039-6dup

The MLH1 c.1039-6dup (p.?) variant has been reported in ClinVar as benign by 5 clinical laboratories and likely benign by 4 clinical laboratories.¹ This variant is present in population databases; in gnomAD v4.1 the overall allele frequency is 0.000530357 and the grpmax filtering allele frequency is 0.00117106, which is above the MLH1 VCEP BA1 threshold of 0.001.² SpliceAI predicts no significant splice effect, with a maximum delta score of 0.01, which is below the BP4 no-impact threshold of 0.1 and below the PP3 splice-defect threshold of 0.2 in the MLH1 VCEP rules.³

BA1 + BP4 → Benign

1 clinvar ↗

2 gnomad_v4 ↗cspec ↗

3 spliceai ↗cspec ↗

Gene diagram · NM_000249.4 · variants mapped to exon structure

MLH1 NM_000249.4

Fetching transcript structure from UCSC…

Applied criteria · 2 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= 0.000530357; MAF= 0.05304%, 653/1231246 alleles, homozygotes = 1) and has highest observed frequency in the African/African American population (AF= 0.00142622; MAF= 0.14262%, 78/54690 alleles, homozygotes = 0); grpmax FAF= 0.00117106.

v2.1

This variant is present in gnomAD v2.1 (AF= 0.000263237; MAF= 0.02632%, 37/140558 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0.000807103; MAF= 0.08071%, 10/12390 alleles, homozygotes = 0); grpmax FAF= 0.00082842.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

0.053% · 653 / 1,231,246
1 hom · FAF 0.12%

African/African American 78 / 54,690	0.14%
Remaining individuals 24 / 45,318	0.053%
European (non-Finnish) 503 / 953,590	0.053%
Admixed American 13 / 31,092	0.042%
East Asian 12 / 33,916	0.035%
Middle Eastern 1 / 3,444	0.029%
Ashkenazi Jewish 6 / 20,848	0.029% 1 hom
European (Finnish) 10 / 44,710	0.022%
South Asian 6 / 42,746	0.014%

+ 1 not observed (Amish)

gnomAD v2.1

0.026% · 37 / 140,558
0 hom · FAF 0.083%

African/African American 10 / 12,390	0.081%
Ashkenazi Jewish 2 / 5,092	0.039%
Remaining individuals 1 / 2,970	0.034%
European (non-Finnish) 18 / 70,584	0.026%
South Asian 4 / 16,438	0.024%
European (Finnish) 2 / 15,848	0.013%

+ 2 not observed (Admixed American, East Asian)

gnomAD v4 ↗ gnomAD v2 ↗

ClinVar

This variant has been reported in ClinVar as Benign (5 clinical laboratories) and as Likely benign (4 clinical laboratories).

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01).

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

7Sources

CSpec VCEP

ClinVar

gnomAD v2.1

gnomAD v4.1

SpliceAI

OncoKB

COSMIC