NM_000143.4:c.434C>G (p.Ser145Ter) is a nonsense variant in exon 4 of the FH gene, a tumor suppressor with established loss-of-function as the disease mechanism for hereditary leiomyomatosis and renal cell cancer (HLRCC). Under ClinGen SVI PVS1 recommendations (PMC6185798), this meets PVS1 at very strong strength.1 The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada population databases (allele frequency 0.0%), meeting PM2 at supporting strength under the generic ACMG/AMP framework.2 This variant is classified as Pathogenic in ClinVar (Variation ID 824814) by 4 independent clinical laboratories, meeting PP5 at supporting strength under the generic ACMG/AMP framework.3 Combined classification: PVS1 (very strong) + PM2 (supporting) + PP5 (supporting). Under ACMG/AMP 2015 combination rules, 1 very strong criterion with 1 or more supporting criteria is sufficient for a Pathogenic classification.4
FH
Final classification
Pathogenic
FH c.434C>G · p.Ser145Ter
FH
NM_000143.4:c.434C>G (p.Ser145Ter) is a nonsense variant in exon 4 of the FH gene, a tumor suppressor with established loss-of-function as the disease mechanism for hereditary leiomyomatosis and renal cell cancer (HLRCC). Under ClinGen SVI PVS1 recommendations (PMC6185798), this meets PVS1 at very strong strength.
gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PVS1 very strong, PM2 supporting, PP5 supporting; combination = 1 very strong + 2 supporting, which maps to Pathogenic.
Classification rationale
PVS1PM2PP5
Pathogenic
FH c.434C>G
PVS1 + PM2 + PP5
→
Pathogenic
1
pvs1_generic_framework ↗pvs1_gene_contextpvs1_variant_assessment
4
generic_acmg_combination_rules
Gene diagram
· NM_000143.4 · variants mapped to exon structure
FH
NM_000143.4
Fetching transcript structure from UCSC…
Applied criteria · 3 applied · 15 assessed
Applied · 3
Strength
Supporting
Moderate
Strong
Very strong
✓
PVS1
very strong
Pathogenic
NM_000143.4:c.434C>G is a nonsense variant predicted to result in premature termination at codon 145 (p.Ser145Ter) in exon 4 of 10. FH is an established tumor suppressor gene with loss-of-function as the disease mechanism for hereditary leiomyomatosis and renal cell cancer (HLRCC). Under the ClinGen SVI PVS1 decision tree (PMC6185798), nonsense variants in genes with established LoF mechanism are assigned PVS1 at very strong strength. The truncation occurs early in the coding sequence (codon 145 of 510) and is predicted to trigger nonsense-mediated decay.
Nonsense variant p.Ser145Ter in exon 4 of 10FH established tumor suppressor with LoF disease mechanism for HLRCCTruncation early in coding sequence
✓
PM2
supporting
Pathogenic
Variant is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0 (allele frequency = 0.0%). Under generic ACMG/AMP framework, complete absence from large population databases meets PM2 at supporting level.
Absent from gnomAD v2.1 (0 alleles)Absent from gnomAD v4.1 (0 alleles)Absent from gnomAD-Canada v1.0 (0 alleles)
✓
PP5
supporting
Pathogenic
This variant is reported as Pathogenic in ClinVar (Variation ID: 824814) by 4 clinical laboratories (Institute for Clinical Genetics TU Dresden, Ambry Genetics, Labcorp/Invitae, Victorian Clinical Genetics Services). Review status is 'criteria provided, single submitter' (1-star, not 3-star expert panel). Under generic ACMG/AMP rules, PP5 is applied at supporting strength when multiple clinical laboratories agree on pathogenicity but no expert panel review exists.
ClinVar Variation ID 824814: Pathogenic4 clinical laboratories with concordant Pathogenic classificationReview status: criteria provided
Assessed · not applied
Pathogenic
PS2
No proband or family data available to assess de novo status for this variant.
PS3
No variant-specific functional studies were identified in any of the reviewed publications.
PS4
The variant is absent from gnomAD population databases.
PM1
The nonsense variant occurs at codon 145 in exon 4.
PM6
No de novo evidence available for this variant in the case materials or reviewed literature.
PP1
No segregation data is available for this variant in the reviewed publications or case materials.
PP4
Phenotype specificity cannot be assessed without patient-specific clinical data in the case materials.
Benign
BA1
Allele frequency is 0.0% in gnomAD v2.1, v4.1, and gnomAD-Canada, far below the >1% threshold for BA1.
BS1
Allele frequency is 0.0% in gnomAD, far below the >0.3% threshold for BS1.
BS2
This variant has not been observed in any healthy adult controls in gnomAD (complete absence).
BS3
No functional studies demonstrate a benign effect.
BS4
No segregation evidence suggesting lack of cosegregation with disease is available.
BP2
No evidence of observation in trans with a known pathogenic dominant variant in FH.
BP5
The variant is reported as Pathogenic in ClinVar by multiple clinical laboratories and is associated with HLRCC through FH loss-of-function.
BP6
ClinVar classification is Pathogenic, not benign.
N/A · 7
PS1 · PM5 · PP2 · PP3 · BP1 · BP4 · BP7
Research & evidence
Population frequency · supports pathogenic
gnomAD v4.1
gnomAD v2.1
v4.1
Absent from gnomAD v4.1.
v2.1
Absent from gnomAD v2.1.
🇨🇦 CA
Absent from gnomAD-Canada v1.0.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
gnomAD v2.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
gnomAD Canada 🇨🇦
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
ClinVar
This variant has been reported in ClinVar as Pathogenic (4 clinical laboratories). (ClinVarID = 824814)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). BayesDel score = 0.652534.
Functional
Likely Oncogenic
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.
COSMIC
Cancer hotspots
Somatic evidence
Not in COSMIC / hotspots
COSMIC
This variant does not lie in a statistically significant hotspot. COSMIC could not be reviewed because the browser session was redirected to the login page before search results were available.
Hotspots
This variant does not lie in a statistically significant hotspot.
Sources & reference links
Triaged references · 6 PMIDs not cited in assessment
11865300 ↗
Germline mutations in FH predispose to dominantly inherited uterine fibroids, skin leiomyomata and papillary renal cell cancer.
ONCOKB
15937070 ↗
Novel mutations in FH and expansion of the spectrum of phenotypes expressed in families with hereditary leiomyomatosis and renal cell cancer.
ONCOKB
12761039 ↗
Genetic and functional analyses of FH mutations in multiple cutaneous and uterine leiomyomatosis, hereditary leiomyomatosis and renal cancer, and fumarate hydratase deficiency.
ONCOKB
12772087 ↗
Mutations in the fumarate hydratase gene cause hereditary leiomyomatosis and renal cell cancer in families in North America.
ONCOKB
21398687 ↗
Novel FH mutations in families with hereditary leiomyomatosis and renal cell cancer (HLRCC) and patients with isolated type 2 papillary renal cell carcinoma.
CLINVAR
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