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.¹ 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.² 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.³ 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.⁴