Submissions for variant NM_000143.4(FH):c.797T>C (p.Met266Thr)

gnomAD frequency: 0.00002  dbSNP: rs764648497

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV002545560	SCV002300524	uncertain significance	not provided	2025-01-29	criteria provided, single submitter	clinical testing	This sequence change replaces methionine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 266 of the FH protein (p.Met266Thr). This variant is present in population databases (rs764648497, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with FH-related conditions. ClinVar contains an entry for this variant (Variation ID: 1510249). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on FH protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics	RCV002423251	SCV002677209	uncertain significance	Hereditary cancer-predisposing syndrome	2024-10-29	criteria provided, single submitter	clinical testing	The p.M266T variant (also known as c.797T>C), located in coding exon 6 of the FH gene, results from a T to C substitution at nucleotide position 797. The methionine at codon 266 is replaced by threonine, an amino acid with similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear.
Laboratory of Molecular Epidemiology of Birth Defects, West China Second University Hospital, Sichuan University	RCV003154232	SCV003843778	likely pathogenic	Ovarian cancer	2022-01-01	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003471264	SCV004197339	uncertain significance	Fumarase deficiency	2023-07-28	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV004785453	SCV005405999	likely benign	Hereditary leiomyomatosis and renal cell cancer	2024-08-29	criteria provided, single submitter	clinical testing	This variant is considered likely benign. This variant has been observed at a population frequency that is significantly greater than expected given the associated disease prevalence and penetrance.