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FHc.434C>GPathogenic
Print report
Variant interpretation report

FH c.434C>G, p.(Ser145Ter)

NM_000143.4:c.434C>G NP_000134.2:p.(Ser145Ter) View identifiers
Classification
Pathogenic

Variant description:

No variant summary was recorded for this case.

Five-step scale from benign to pathogenic. This variant is pathogenic. Select a step to read what it means.

Pathogenic.A pathogenic classification under the recorded framework.

In plain language

Gene-level background from the recorded interpretation.

About FH

No gene-level summary was recorded for this case.

LYFE Sciences is an AI system, and it can make mistakes. Criteria may be applied incorrectly, sources may be misread, and a confident-looking classification can still be wrong. Double-check every criterion and its underlying evidence before relying on any call.
01The reasoning

How it was classified

The recorded framework is Not recorded. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.

Recorded applied criteria

The applied criteria and their strengths are shown as assessed under the stated framework.

Pathogenic evidence criteria: 3 Benign evidence criteria: 0
Pathogenic criteria applied · 3
PVS1Very strong
PVS1 · very strong

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.

PM2Supporting
PM2 · supporting

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.

PP5Supporting
PP5 · supporting

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.

Benign criteria applied · 0

No benign criterion marked as applied in the recorded assessment.

Recorded classification: Pathogenic

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.

02The sources

Evidence at a glance

Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.

SpliceAI score
0.010 maximum delta

Recorded SpliceAI maximum delta score: 0.010. Refer to the recorded PP3/BP4 rationale for interpretation.

No listed criterion applied SpliceAI ↗
ClinVar submissions
4 reported laboratory submissions

4 Pathogenic. ClinVar API review status: criteria provided, multiple submitters, no conflicts.

Applied · PP5 → ClinVar ↗
Functional evidence
Statement recorded

OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.

No listed criterion applied OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
No matching record reported

COSMIC could not be reviewed because the browser session was redirected to the login page before search results were available.

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.

Context only
COSMIC ↗Cancer Hotspots ↗
For specialists

Technical detail

ACMG/AMP criteria under Not recorded, with the data and sources behind each one.

26 criteria with recorded statuses: 3 met · 13 not met · 2 not assessed · 8 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic
PVS1PS1PS2PS3PS4PM1PM2PM5PM6PP1PP2PP3PP4PP5PS5
Benign
BA1BS1BS2BS3BS4BP1BP2BP4BP5BP6BP7
Met Not met Not assessed Not applicable

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.

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.

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.

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.

Met · 3

PVS1 Very strongNM_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. Details ▾Hide ▴
Evidence considered
  • Nonsense variant p.Ser145Ter in exon 4 of 10
  • FH established tumor suppressor with LoF disease mechanism for HLRCC
  • Truncation early in coding sequence
  • predicted to trigger NMD
  • ClinGen SVI PVS1 framework (PMC6185798) assigns very strong for nonsense variants in LoF-established genes
Sources
pvs1_generic_framework ↗pvs1_gene_contextpvs1_variant_assessment
PM2 SupportingVariant 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. Details ▾Hide ▴
Evidence considered
  • Absent from gnomAD v2.1 (0 alleles)
  • Absent from gnomAD v4.1 (0 alleles)
  • Absent from gnomAD-Canada v1.0 (0 alleles)
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
PP5 SupportingThis 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. Details ▾Hide ▴
Evidence considered
  • ClinVar Variation ID 824814: Pathogenic
  • 4 clinical laboratories with concordant Pathogenic classification
  • Review status: criteria provided
  • single submitter (1-star)
Still missing
  • No expert panel review (not 3-star)
Sources
clinvar ↗

Not met · 13 · evaluated, threshold not reached

PS3 No variant-specific functional studies were identified in any of the reviewed publications. Full-text papers (PMID:11865300, PMID:15937070, PMID:12772087, PMID:21398687) describe FH enzymatic activity assays for other variants but c.434C>G / p.Ser145Ter was not tested. OncoKB annotation of 'Likely Loss-of-function' is derived from variant type (nonsense), not direct experimental data for this variant. Details ▾Hide ▴
Evidence considered
  • OncoKB: Likely Loss-of-function based on variant type
  • not direct experimental data
  • No variant-specific functional assays identified in the literature
Still missing
  • No experimental functional data for c.434C>G specifically
Sources
oncokb ↗
PS4 The variant is absent from gnomAD population databases. ClinVar submissions indicate observation in clinical testing populations (4 laboratories classify as Pathogenic) but no systematic case-control or prevalence data demonstrating statistically significant enrichment in affected versus unaffected individuals is available in the case materials. Details ▾Hide ▴
Evidence considered
  • ClinVar: 4 clinical laboratories reporting Pathogenic
  • No case-control or prevalence study data available
Still missing
  • No formal PS4 case-control data
Sources
clinvar ↗gnomad_v2 ↗gnomad_v4 ↗
PM1 The nonsense variant occurs at codon 145 in exon 4. FH has a well-characterized fumarate lyase domain, but this specific residue is not in a statistically significant mutational hotspot per cancerhotspots.org. The predominant germline mutational hotspots in FH are reported in exons 5 and 7. For a truncating variant where PVS1 is already applied at very strong strength, PM1 would constitute double-counting of domain-level evidence. Details ▾Hide ▴
Evidence considered
  • Not a statistically significant hotspot per cancerhotspots.org
  • Predominant FH hotspots in exons 5 and 7
  • not exon 4
Sources
pvs1_gene_context
PP1 No segregation data is available for this variant in the reviewed publications or case materials. Details ▾Hide ▴
Still missing
  • No family segregation data available
PP4 Phenotype specificity cannot be assessed without patient-specific clinical data in the case materials. Details ▾Hide ▴
Still missing
  • No patient-specific phenotype data provided
BA1 Allele frequency is 0.0% in gnomAD v2.1, v4.1, and gnomAD-Canada, far below the >1% threshold for BA1. Details ▾Hide ▴
Evidence considered
  • gnomAD allele frequency: 0.0%
Sources
gnomad_v2 ↗gnomad_v4 ↗
BS1 Allele frequency is 0.0% in gnomAD, far below the >0.3% threshold for BS1. Details ▾Hide ▴
Evidence considered
  • gnomAD allele frequency: 0.0%
Sources
gnomad_v2 ↗gnomad_v4 ↗
BS2 This variant has not been observed in any healthy adult controls in gnomAD (complete absence). BS2 requires observation in healthy adults, particularly in a homozygous or hemizygous state. Details ▾Hide ▴
Evidence considered
  • Variant not observed in any gnomAD individual
Sources
gnomad_v2 ↗gnomad_v4 ↗
BS3 No functional studies demonstrate a benign effect. OncoKB classifies this variant as 'Likely Loss-of-function' based on the predicted protein-truncating consequence, which is consistent with a damaging rather than benign effect. Details ▾Hide ▴
Evidence considered
  • OncoKB: Likely Loss-of-function
  • Likely Oncogenic
  • No benign functional data identified
Sources
oncokb ↗
BS4 No segregation evidence suggesting lack of cosegregation with disease is available. Details ▾Hide ▴
Still missing
  • No segregation data
BP2 No evidence of observation in trans with a known pathogenic dominant variant in FH. BP2 requires documented observation in trans. Details ▾Hide ▴
Still missing
  • No data on trans configuration
BP5 The variant is reported as Pathogenic in ClinVar by multiple clinical laboratories and is associated with HLRCC through FH loss-of-function. BP5 requires a variant to be found in a case with an alternate molecular basis for disease. Details ▾Hide ▴
Evidence considered
  • ClinVar: Pathogenic
  • No alternative molecular basis documented
Sources
clinvar ↗
BP6 ClinVar classification is Pathogenic, not benign. BP6 requires a reputable source to classify as benign. Details ▾Hide ▴
Evidence considered
  • ClinVar: Pathogenic (not benign)
Sources
clinvar ↗

Not assessed · 2 · no assessment recorded

PS2 No proband or family data available to assess de novo status for this variant. Details ▾Hide ▴
Still missing
  • No patient-specific de novo data in case materials
PM6 No de novo evidence available for this variant in the case materials or reviewed literature. Details ▾Hide ▴
Still missing
  • No patient-specific de novo data
Not applicable · 8· recorded as not applicable Show reasons ▾Hide reasons ▴
PS1 N/APS1 applies to same amino acid missense changes previously established as pathogenic. This is a nonsense (stop-gain) variant; PS1 does not apply to protein-truncating variants. Details ▾Hide ▴

No further detail was recorded.

PM5 N/AThis is a nonsense (stop-gain) variant at codon 145. The PM5 candidates analysis could not confirm classic same-residue PM5 semantics. A different nucleotide change at position 434 (A434G → N145S, missense) was reported in Toro et al. 2003 (PMID:12772087) but this is a different variant type (missense) and PM5 comparison does not apply between nonsense and missense variants at the same codon under the standard framework. Details ▾Hide ▴
Evidence considered
  • Nonsense variant p.Ser145Ter — no same-residue pathogenic missense comparator available
  • A434G in Toro 2003 is a different nucleotide and amino acid change (N145S
  • missense)
Sources
pm5_candidates
PP2 N/APP2 applies to missense variants in genes with low rate of benign missense variation and few pathogenic missense variants. This is a nonsense (stop-gain) variant; PP2 is not applicable to protein-truncating variants. Details ▾Hide ▴

No further detail was recorded.

PP3 N/AFor protein-truncating variants where PVS1 is applied, in silico predictors are not independently informative beyond the established loss-of-function mechanism. BayesDel score (0.653) and SpliceAI (max delta 0.01) are noted but applying PP3 would constitute double-counting of the same molecular evidence captured by PVS1. Details ▾Hide ▴
Evidence considered
  • BayesDel: 0.653
  • SpliceAI max delta: 0.01 (no splice impact)
Sources
bayesdelspliceai ↗
BP1 N/ABP1 applies to missense variants in genes where the primary disease mechanism is truncating. This is a truncating (nonsense) variant itself; BP1 is not applicable. Details ▾Hide ▴

No further detail was recorded.

BP4 N/ABP4 requires multiple lines of computational evidence suggesting no impact on gene or gene product. For a nonsense variant producing a premature stop codon, the primary deleterious mechanism is protein truncation. Computational splicing predictions (SpliceAI max delta 0.01) do not alter this conclusion. BP4 is not typically applied to protein-truncating variants. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta: 0.01 (no cryptic splice effect)
Sources
spliceai ↗
BP7 N/ABP7 is for synonymous or intronic variants with no predicted splice impact. This is a nonsense (stop-gain) variant leading to premature termination; BP7 is not applicable. Details ▾Hide ▴

No further detail was recorded.

PS5 N/APS5 requires a pathogenic variant at the same nucleotide position demonstrated in an independent family using an independent detection method. No such evidence is available in the case materials. Details ▾Hide ▴

No further detail was recorded.

Identifiers

Gene
FH
Transcript
NM_000143.4
Coding (HGVS c.)
NM_000143.4:c.434C>G
Protein (HGVS p.)
NP_000134.2:p.(Ser145Ter)
GRCh38
chr1:241512088 G>C
GRCh37
chr1:241675388 G>C
ClinVar
824814

Gene diagram

Every interpreted variant in FH, mapped onto the exon structure of NM_000143.4. Select a row to find it on the plot.

FHNM_000143.4
Fetching transcript structure from UCSC…
gnomAD v4.1 Allele count data not recorded
gnomAD v2.1 Allele count data not recorded
gnomAD-Canada v1.0 Allele count data not recorded

Statements

gnomAD v4.1

Absent from gnomAD v4.1.

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

SpliceAI and Pangolin

SpliceAI acceptor lossat +7 bp
0.010
SpliceAI acceptor gainat +51 bp
0.010
SpliceAI donor lossat -121 bp
0.000
SpliceAI donor gainat +46 bp
0.000
Pangolin splice lossmagnitude shown
-0.040
Pangolin splice gain
0.010

Other predictors

REVEL
Not available
BayesDel
0.653

How the predictions were used

PP3 N/AFor protein-truncating variants where PVS1 is applied, in silico predictors are not independently informative beyond the established loss-of-function mechanism. BayesDel score (0.653) and SpliceAI (max delta 0.01) are noted but applying PP3 would constitute double-counting of the same molecular evidence captured by PVS1. Details ▾Hide ▴
Evidence considered
  • BayesDel: 0.653
  • SpliceAI max delta: 0.01 (no splice impact)
Sources
bayesdelspliceai ↗
BP4 N/ABP4 requires multiple lines of computational evidence suggesting no impact on gene or gene product. For a nonsense variant producing a premature stop codon, the primary deleterious mechanism is protein truncation. Computational splicing predictions (SpliceAI max delta 0.01) do not alter this conclusion. BP4 is not typically applied to protein-truncating variants. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta: 0.01 (no cryptic splice effect)
Sources
spliceai ↗
BP7 N/ABP7 is for synonymous or intronic variants with no predicted splice impact. This is a nonsense (stop-gain) variant leading to premature termination; BP7 is not applicable. Details ▾Hide ▴

No further detail was recorded.

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). BayesDel score = 0.652534.

6 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata. None of the listed paper records explicitly indicates that the variant is named.

Recorded publications

  • Germline mutations in FH predispose to dominantly inherited uterine fibroids, skin leiomyomata and papillary renal cell cancer.
    Tomlinson IP et al. · 2002
    Tomlinson et al. identified FH as the causative gene for multiple cutaneous and uterine leiomyomatosis and reported 25 germline mutations in 42 probands, including protein-truncating mutations, large deletions, and missense changes. NM_000143.4:c.434C>G (p.Ser145Ter) was not among the reported mutations.
    Does not name this variant
    PMID 11865300 ↗
  • Novel mutations in FH and expansion of the spectrum of phenotypes expressed in families with hereditary leiomyomatosis and renal cell cancer.
    Wei MH et al. · 2006
    Wei et al. characterized 21 new HLRCC families and identified 14 FH germline mutations (10 missense, 1 insertion, 2 nonsense, 1 splice site), including the novel nonsense mutation S102X. NM_000143.4:c.434C>G (p.Ser145Ter) was not among the reported mutations. FH enzymatic activity was shown to be reduced in lymphoblastoid cells from patients with FH mutations, supporting loss-of-function as the disease mechanism.
    Does not name this variant
    PMID 15937070 ↗
  • Genetic and functional analyses of FH mutations in multiple cutaneous and uterine leiomyomatosis, hereditary leiomyomatosis and renal cancer, and fumarate hydratase deficiency.
    Alam et al. reported additional FH mutations in multiple cutaneous and uterine leiomyomatosis and fumarate hydratase deficiency patients and performed functional analyses. NM_000143.4:c.434C>G (p.Ser145Ter) was not identifiable in the available abstract; full text was not available for confirmation.
    Does not name this variant
    PMID 12761039 ↗
  • Mutations in the fumarate hydratase gene cause hereditary leiomyomatosis and renal cell cancer in families in North America.
    Toro et al. screened 35 North American families with cutaneous leiomyomas and identified 20 different FH mutations, with mutations found in 31 families (89%). A missense change at nucleotide position 434 (A434G → N145S) was reported in family 253, but this represents a different nucleotide substitution resulting in a missense change (Asn145Ser), not the nonsense variant c.434C>G (p.Ser145Ter) under review.
    Does not name this variant
    PMID 12772087 ↗
    Quoted passage
    A434G — N145S — Missense

    Table 1, family 253 (A434G → N145S)

  • Novel FH mutations in families with hereditary leiomyomatosis and renal cell cancer (HLRCC) and patients with isolated type 2 papillary renal cell carcinoma.
    Gardie B et al. · 2011
    Gardie et al. performed comprehensive FH genetic and functional analysis in 56 families with HLRCC and 23 patients with isolated type 2 papillary RCC, identifying 32 different germline FH mutations including 21 novel. All tested mutations demonstrated significant reduction of FH enzymatic activity, supporting loss-of-function and haploinsufficiency. NM_000143.4:c.434C>G (p.Ser145Ter) was not among the reported mutations.
    Does not name this variant
    PMID 21398687 ↗
  • 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.
    Richards S et al. · 2015
    Richards et al. published the ACMG/AMP standards and guidelines for interpretation of sequence variants. This is a methodological guideline document and does not discuss any specific FH variants.
    Does not name this variant
    PMID 25741868 ↗

Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.

gnomAD v4.1 Captured gnomAD v4.1 source record Open source ↗
gnomAD v2.1 Captured gnomAD v2.1 source record Open source ↗
SpliceAI Lookup Recorded maximum delta 0.010 Open source ↗
ClinVar 4 Pathogenic Open source ↗
COSMIC Captured COSMIC source record Open source ↗
Cancer hotspots Captured Cancer Hotspots source record Open source ↗
OncoKB Captured OncoKB source record Open source ↗

All source links

Statements for reports

The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.

gnomAD v4.1

Absent from gnomAD v4.1.

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

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

OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.

Somatic

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.

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.