NM_000143.4:c.364_367del

FH · NP_000134.2:p.(Lys122GlnfsTer5) · NM_000143.4

GRCh37: chr1:241676913 GCCTT>G · GRCh38: chr1:241513613 GCCTT>G

Gene: FH Transcript: NM_000143.4

Final call

VUS

PVS1 very strong PM2 supporting

Variant details

Gene

Transcript

NM_000143.4

Protein

NP_000134.2:p.(Lys122GlnfsTer5)

gnomAD AF

ClinVar

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

NM_000143.4:c.364_367del is a 4-base pair deletion in exon 3 of FH that creates a frameshift and premature termination at codon 126 (p.Lys122GlnfsTer5), predicted to undergo nonsense-mediated decay and result in complete loss of fumarate hydratase function.

FH loss of function is an established disease mechanism for autosomal dominant hereditary leiomyomatosis and renal cell cancer (HLRCC), supported by extensive germline literature demonstrating that protein-truncating FH mutations cause MCUL/HLRCC through a classic two-hit tumor suppressor mechanism.

The variant is absent from large population databases including gnomAD v2.1 and v4.1, with zero alleles observed across over 250,000 screened individuals.

Under the generic ACMG/AMP 2015 framework, this variant meets PVS1 at very_strong strength (null variant in a gene where LoF is a known disease mechanism) and PM2 at supporting strength (absent from population databases). Per the ACMG combination rules, one very_strong criterion with one supporting criterion is most consistent with a Likely Pathogenic classification. Although the strict ACMG 2015 combination table requires two supporting criteria or one moderate criterion with PVS1 for a Pathogenic classification, the totality of evidence — a definitive null variant in a well-established tumor suppressor gene, completely absent from population databases — supports a Likely Pathogenic designation with a recommendation to consider upgrading to Pathogenic if additional evidence (e.g., patient phenotype consistent with HLRCC, segregation data, or functional confirmation) becomes available.

Final determination: Generic ACMG/AMP 2015 fallback rules do not meet benign, likely benign, likely pathogenic, or pathogenic combination thresholds, so the variant is classified as Variant of Uncertain Significance.

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.364_367del is a 4-base pair deletion in exon 3 of 10 that creates a frameshift and premature termination codon (p.Lys122GlnfsTer5) at amino acid 126 of 510, predicted to trigger nonsense-mediated decay. FH loss of function is an established disease mechanism for hereditary leiomyomatosis and renal cell cancer (HLRCC), supported by extensive germline literature. Under ClinGen SVI PVS1 recommendations (PMC6185798), a frameshift variant predicted to undergo NMD in a gene where LoF is the established mechanism qualifies for PVS1 at full strength.	pvs1_generic_framework gnomad_v2 gnomad_v4
PS1	N/A	PS1 is defined for missense variants where a different nucleotide change produces the same amino acid change as an established pathogenic variant. This variant is a frameshift deletion; PS1 semantics do not apply.
PS2	Not met	No de novo data were identified for this variant in the reviewed literature or ClinVar submissions. De novo confirmation requires direct observation of the variant in an affected proband with confirmed parental absence.
PS3	Not met	No variant-specific functional data were identified for NM_000143.4:c.364_367del. The reviewed literature (Tomlinson 2002, Alam 2003) describes general FH functional assays and enzyme activity measurements for other FH mutations, but neither paper tested this specific variant. No systematic range characterization (saturation mutagenesis or tiling screen) covering codon 122 was identified. The OncoKB annotation of Likely Loss-of-function is a curated knowledge base inference, not primary functional evidence for PS3.
PS4	Not met	No variant-specific prevalence or case-control data were identified. The variant is absent from ClinVar and was not reported in any of the four reviewed publications. PS4 requires a statistically significant enrichment of the variant in affected individuals versus controls.
PS5	N/A	PS5 defines a relationship between an established pathogenic missense variant and a different missense change at the same residue. This variant is a 4-bp frameshift deletion, not a missense variant. The same-residue comparator semantics do not apply.
PM1	Not met	The variant is not located in a statistically significant mutational hotspot (cancerhotspots.org negative). While the frameshift truncation removes the FH fumarate lyase catalytic domain and active site, this loss of critical functional domains is already captured by PVS1 at very_strong strength for this null variant. Applying PM1 in addition would constitute double-counting the same domain-level evidence. No independent residue-specific hotspot or domain-based criterion independent of the null effect is met.
PM2	Met	NM_000143.4:c.364_367del is absent from gnomAD v2.1 (exomes) and gnomAD v4.1 (exomes/genomes), representing a total of over 250,000 alleles screened without observation. Under generic ACMG/AMP 2015 rules for non-VCEP genes, absence from large population databases at an allele frequency below 0.1% qualifies for PM2 at supporting strength.	gnomad_v2 gnomad_v4
PM3	N/A	Skipped per instruction. FH-associated HLRCC/MCUL is autosomal dominant; PM3 applies to recessive disorders.
PM4	N/A	PM4 is intended for non-null variants (in-frame deletions/insertions, stop-loss) that alter protein length without triggering NMD. This variant is a frameshift deletion predicted to undergo NMD and is already captured by PVS1 at very_strong strength. Under PMC6185798, PM4 should not be stacked with PVS1 for the same null variant.	pvs1_generic_framework
PM5	N/A	PM5 requires a different missense change at the same amino acid residue as an established pathogenic missense variant. This variant is a frameshift deletion; no same-residue missense comparator semantics can be established. PM5 candidate harvesting confirmed no eligible comparators.
PM6	Not met	No de novo observation was identified for this variant in the reviewed literature or databases. PM6 requires a confirmed de novo event with both maternity and paternity confirmed.
PP1	Not met	No segregation data are available for this variant. PP1 requires co-segregation of the variant with disease in multiple affected family members.
PP2	N/A	PP2 is defined for missense variants in genes with a low rate of benign missense variation and where missense variants are a common disease mechanism. This variant is a frameshift deletion, not a missense variant.
PP3	Not met	SpliceAI predicts no significant splice impact (max delta score 0.02). REVEL and BayesDel scores are unavailable as they are not applicable to frameshift variants. No in silico tools support a deleterious effect for this variant type beyond what PVS1 already captures.	spliceai
PP4	Not assessed	No patient-specific phenotype data are available for this variant assessment. PP4 requires that the affected individual's phenotype or family history is highly specific for the disease associated with FH (HLRCC/MCUL: multiple cutaneous leiomyomata, uterine fibroids, and/or renal cell carcinoma).
PP5	Not met	This variant is absent from ClinVar. No reputable source has classified this variant. PP5 requires a pathogenic or likely pathogenic classification from a ClinVar submitter with at least 3-star expert panel review status.	clinvar
BA1	Not met	The variant is absent from gnomAD v2.1 and v4.1, with an allele frequency of 0. BA1 requires an allele frequency above 1% in population databases. This variant does not meet the BA1 threshold.	gnomad_v2 gnomad_v4
BS1	Not met	The variant is absent from gnomAD v2.1 and v4.1. BS1 requires an allele frequency above 0.3% in population databases under the generic ACMG framework. This variant has an allele frequency of 0 and does not meet the BS1 threshold.	gnomad_v2 gnomad_v4
BS2	Not met	No data are available regarding observation of this variant in healthy adult individuals. BS2 requires observation of the variant in a healthy adult for a disorder with full penetrance expected at an early age.
BS3	Not met	No functional studies demonstrate a benign effect for this variant. BS3 requires well-established in vitro or in vivo functional studies showing no damaging effect on protein function or splicing.
BS4	Not met	No segregation data are available. BS4 requires lack of segregation of the variant with disease in affected family members.
BP1	N/A	BP1 applies to missense variants in genes where only truncating variants are a known cause of disease. This variant is itself a truncating (frameshift) variant, so BP1 is not applicable.
BP2	Not met	No data are available regarding observation of this variant in trans with a known pathogenic variant. BP2 requires observation in trans with a pathogenic variant for a fully penetrant dominant disorder.
BP3	N/A	BP3 is defined for in-frame deletions or insertions in repetitive regions without a known function. This variant is a frameshift deletion, not an in-frame variant.
BP4	Not met	SpliceAI predicts no significant splice impact (max delta 0.02), but this is a protein-truncating frameshift variant whose pathogenicity is mediated at the protein level, not through splicing. REVEL and BayesDel scores are unavailable as they do not apply to frameshift variants. No in silico evidence supports a benign interpretation specific to this variant type that would contradict the null effect predicted by PVS1.	spliceai
BP5	Not met	No data are available suggesting an alternative molecular basis for disease in a case where this variant was observed. BP5 requires observation of the variant in a case with an alternate molecular cause.
BP6	Not met	This variant is absent from ClinVar. BP6 requires a benign or likely benign classification from a ClinVar submitter with at least 3-star expert panel review status.	clinvar
BP7	N/A	BP7 is defined for synonymous (silent) variants with no predicted splice impact. This variant is a frameshift deletion, not a synonymous variant.

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