Variant classification summary

NM_000143.4:c.434C>G

FH · NP_000134.2:p.(Ser145Ter) · NM_000143.4

GRCh37: chr1:241675388 G>C · GRCh38: chr1:241512088 G>C

Gene: FH Transcript: NM_000143.4

Final call

Pathogenic

PVS1 very strong PM2 supporting PP5 supporting

Variant details

Gene

FH

Transcript

NM_000143.4

Protein

NP_000134.2:p.(Ser145Ter)

gnomAD AF

ClinVar

Pathogenic

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

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.

2

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.

3

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.

4

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.

Final determination: Generic ACMG/AMP 2015 fallback rules support a Pathogenic classification based on the observed combination of very strong, strong, moderate, and supporting pathogenic criteria.

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
PVS1	Met	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.	pvs1_generic_framework pvs1_gene_context pvs1_variant_assessment
PS1	N/A	PS1 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.
PS2	Not assessed	No proband or family data available to assess de novo status for this variant.
PS3	Not met	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.	oncokb
PS4	Not met	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.	clinvar gnomad_v2 gnomad_v4
PS5	N/A	PS5 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.
PM1	Not met	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.	pvs1_gene_context
PM2	Met	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.	gnomad_v2 gnomad_v4 gnomad_canada
PM5	N/A	This 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.	pm5_candidates
PM6	Not assessed	No de novo evidence available for this variant in the case materials or reviewed literature.
PP1	Not met	No segregation data is available for this variant in the reviewed publications or case materials.
PP2	N/A	PP2 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.
PP3	N/A	For 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.	bayesdel spliceai
PP4	Not met	Phenotype specificity cannot be assessed without patient-specific clinical data in the case materials.
PP5	Met	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
BA1	Not met	Allele frequency is 0.0% in gnomAD v2.1, v4.1, and gnomAD-Canada, far below the >1% threshold for BA1.	gnomad_v2 gnomad_v4
BS1	Not met	Allele frequency is 0.0% in gnomAD, far below the >0.3% threshold for BS1.	gnomad_v2 gnomad_v4
BS2	Not met	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.	gnomad_v2 gnomad_v4
BS3	Not met	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.	oncokb
BS4	Not met	No segregation evidence suggesting lack of cosegregation with disease is available.
BP1	N/A	BP1 applies to missense variants in genes where the primary disease mechanism is truncating. This is a truncating (nonsense) variant itself; BP1 is not applicable.
BP2	Not met	No evidence of observation in trans with a known pathogenic dominant variant in FH. BP2 requires documented observation in trans.
BP4	N/A	BP4 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.	spliceai
BP5	Not met	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.	clinvar
BP6	Not met	ClinVar classification is Pathogenic, not benign. BP6 requires a reputable source to classify as benign.	clinvar
BP7	N/A	BP7 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.

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