Classification rationale

PM2PP3 VUS

FH c.1366G>T

The FH c.1366G>T (p.Val456Leu) variant has been reported in ClinVar as a variant of uncertain significance by one clinical laboratory.¹ This variant is rare in population databases, with gnomAD v2.1 AF 0.00318% (1/31,398 alleles) and gnomAD v4.1 AF 0.00019% (3/1,614,014 alleles), which are both below the 0.1% PM2 threshold and well below the BS1 and BA1 frequency thresholds.² Computational evidence supports a deleterious missense effect, with REVEL 0.913 and BayesDel 0.286106, while SpliceAI predicts no significant splice impact for this variant (max delta score 0.00).³

PM2 + PP3 → VUS

1 clinvar ↗

2 gnomad_v2 ↗gnomad_v4 ↗

3 revelbayesdelspliceai ↗

Gene diagram · NM_000143.4 · variants mapped to exon structure

FH NM_000143.4

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

gnomAD v4.1

gnomAD v2.1

v4.1

This variant is present in gnomAD v4.1 (AF= 1.85872e-06; MAF= 0.00019%, 3/1614014 alleles, homozygotes = 0) and has highest observed frequency in the European (Finnish) population (AF= 4.68589e-05; MAF= 0.00469%, 3/64022 alleles, homozygotes = 0).

v2.1

This variant is present in gnomAD v2.1 (AF= 3.18492e-05; MAF= 0.00318%, 1/31398 alleles, homozygotes = 0) and has highest observed frequency in the European (Finnish) population (AF= 0.000287687; MAF= 0.02877%, 1/3476 alleles, homozygotes = 0).

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

0.00019% · 3 / 1,614,014
0 hom

European (Finnish)

3 / 64,022

0.0047%

+ 9 not observed (Remaining individuals, Admixed American, Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American, European (non-Finnish))

gnomAD v2.1

0.0032% · 1 / 31,398
0 hom

European (Finnish)

1 / 3,476

0.029%

+ 7 not observed (African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (non-Finnish), Remaining individuals, South Asian)

gnomAD v4 ↗ gnomAD v2 ↗

ClinVar

This variant has been reported in ClinVar as Uncertain significance (1 clinical laboratory). (ClinVarID = 4257325)

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.913. BayesDel score = 0.286106.

SpliceAI ↗

Functional Unknown Oncogenic Effect

OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. FH, an enzyme that converts fumarate to malate in the TCA cycle, is infrequently altered in cancer.

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

7Sources

ClinVar

gnomAD v2.1

gnomAD v4.1

SpliceAI

OncoKB

COSMIC

Cancer hotspots

Triaged references · 1 PMID not cited in assessment

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