Classification rationale

BP4BP7 Likely Benign

MLH1 c.1515T>C

The MLH1 c.1515T>C (p.Ser505=) variant has not been observed in somatic cancers in COSMIC and has been reported in ClinVar predominantly as likely benign or benign.¹ This variant is present in gnomAD, including 5/1614044 alleles overall in v4.1 (AF 0.00000310) and 4/44880 East Asian alleles (AF 0.0000891), with a grpmax filtering allele frequency of 0.0000298 that is below the BA1 and BS1 thresholds.² In silico splicing analysis predicts no significant splice impact with a SpliceAI max delta score of 0.00, supporting BP4 for a synonymous variant; no MLH1 HCI prior entry for c.1515T>C was identified, and the available REVEL score was 0.343.³

BP4 + BP7 → Likely Benign

1 clinvar ↗

2 gnomad_v2 ↗gnomad_v4 ↗cspec ↗

3 spliceai ↗revelvcep_hci_priors_mlh1cspec ↗

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= 3.09781e-06; MAF= 0.00031%, 5/1614044 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 8.91266e-05; MAF= 0.00891%, 4/44880 alleles, homozygotes = 0); grpmax FAF= 2.978e-05.

v2.1

This variant is present in gnomAD v2.1 (AF= 1.98829e-05; MAF= 0.00199%, 5/251472 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 0.000217462; MAF= 0.02175%, 4/18394 alleles, homozygotes = 0); grpmax FAF= 7.353e-05.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

0.00031% · 5 / 1,614,044
0 hom · FAF 0.003%

East Asian 4 / 44,880	0.0089%
European (non-Finnish) 1 / 1,180,006	8.5e-05%

+ 8 not observed (Remaining individuals, Admixed American, European (Finnish), Amish, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American)

gnomAD v2.1

0.002% · 5 / 251,472
0 hom · FAF 0.0074%

East Asian 4 / 18,394	0.022%
European (non-Finnish) 1 / 113,748	0.00088%

+ 6 not observed (African/African American, Admixed American, Ashkenazi Jewish, European (Finnish), Remaining individuals, South Asian)

gnomAD v4 ↗ gnomAD v2 ↗

ClinVar

This variant has been reported in ClinVar as Likely benign (5 clinical laboratories) and as Likely Benign (1 clinical laboratory) and as Benign (1 clinical laboratory).

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.343.

SpliceAI ↗

Functional Unknown Oncogenic Effect

OncoKB identified curated literature and non-variant-specific oncogenicity context for review; listed oncogenicity label: Unknown Oncogenic Effect.

OncoKB ↗

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.

COSMIC ↗ Hotspots ↗

Sources & reference links

8Sources

CSpec VCEP

ClinVar

gnomAD v2.1

gnomAD v4.1

SpliceAI

OncoKB

COSMIC

Cancer hotspots