Gene Validity Curation

FH - hereditary leiomyomatosis and renal cell cancer

Gene: FH (HGNC:3700)
Classification - 05/14/2020
Disease: hereditary leiomyomatosis and renal cell cancer (MONDO_0007888)
Mode of Inheritance: Autosomal dominant inheritance (HP:0000006)
Replication over time: YES Contradictory Evidence: NO
Expert Panel: Hereditary Cancer EP
Evidence Summary: Heterozygous variants in the fumarate hydratase (FH) gene are associated with the autosomal dominant disorder hereditary leiomyomatosis and renal cell cancer (HLRCC). This was first proposed by Tomlinson et al in 2002 (PMID: 11865300). Numerous genetic studies have reported familial segregation of FH variants in families with leiomyomatosis or renal cell cancer. Affected individuals with heterozygous mutations had decreased fumarate hydratase enzyme activity in their lymphoblastoid cell lines although penetrance varies among individuals with similar decreases in FH activity. Tumors from HLRCC patients with a FH germline heterozygous mutations presented markedly reduced enzyme activity due to a second hit on FH, compared with tumors with similar histology from non HLRCC patients. There are substantial other functional assays demonstrating deficiency of FH activity and abnormality in smooth muscle differentiation. In summary, FH is definitively associated with HLRCC. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time.
Genetic Evidence
Case-Level Data
Evidence Type Case Information Type Guidelines Points PMIDs/Notes
Default Range Max Count Total Counted
Variant Evidence
Autosomal Dominant or X-linked Disorder Variant is de novo 2 0-3 12
Proband with predicted or proven null variant 1.5 0-2 10 5 7.5 7.5
Tomlinson IP et al. 2002 Apr (PMID:11865300); Martinez-Mir A et al. 2003 Oct (PMID:14632190); Wheeler KC et al. 2016 Jan (PMID:26493120);
Proband with other variant type with some evidence of gene impact 0.5 0-1.5 7 7
3
3
Tomlinson IP et al. 2002 Apr (PMID:11865300); Smit DL et al. 2011 Jan (PMID:20618355); Kuwada M et al. 2014 Mar 31 (PMID:24684806); Yamasaki T et al. 2011 Mar (PMID:21304509); Martinez-Mir A et al. 2003 Oct (PMID:14632190); van Spaendonck-Zwarts KY et al. 2012 Mar (PMID:22086304);
Autosomal Recessive Disease Two variants in trans and at least one de novo or a predicted/proven null variant 2 0-3 12
Two variants (not predicted/proven null) with some evidence of gene impact in trans 1 0-1.5
Segregation Evidence   Summed LOD Family Count 1.5 1.5  
Candidate gene sequencing 10.47 3
Tomlinson IP et al. 2002 Apr (PMID:11865300); Smit DL et al. 2011 Jan (PMID:20618355); Martinez-Mir A et al. 2003 Oct (PMID:14632190);
Exome/genome or all genes sequenced in linkage region
Total Summed LOD Score 10.47    
Case-Control Data
Case-Control Study Type Case-Control Quality Criteria Guidelines Points PMIDs/Notes
Points/Study Max Count Points Counted
Single Variant Analysis 1. Variant Detection Methodology
2. Power
3. Bias and confounding
4. Statistical Significance
0-6 12
Aggregate Variant Analysis 0-6
Total Genetic Evidence Points (Maximum 12) 12
Experimental Evidence
Evidence Category Evidence Type Guidelines Points PMIDs/Notes
Default Range Max Count Total Counted
Function Biochemical Function 0.5 0 - 2 2 1
0.5
0.5
Pithukpakorn M et al. 2006 Sep (PMID:16597677);
Protein Interaction 0.5 0 - 2
Expression 0.5 0 - 2
Functional Alteration Patient cells 1 0 - 2 2 3
3
2
Tomlinson IP et al. 2002 Apr (PMID:11865300); Yang Y et al. 2010 Jan 1 (PMID:19963135); Adam J et al. 2011 Oct 18 (PMID:22014577);
Non-patient cells 0.5 0 - 1
Models Non-human model organism 2 0 - 4 4 1
Cell culture model 1 0 - 2
Rescue Rescue in human 2 0 - 4
Rescue in non-human model organism 2 0 - 4
Rescue in cell culture model 1 0 - 2 1 1
O'Flaherty L et al. 2010 Oct 1 (PMID:20660115);
Rescue in patient cells 1 0 - 2
Total Experimental Evidence Points (Maximum 6) 3.5

 


 

Assertion criteria Genetic Evidence (0-12 points) Experimental Evidence
(0-6 points)
Total Points
(0-18)
Replication Over Time (Y/N)
Description Case-level, family segregation, or case-control data that support the gene-disease association Gene-level experimental evidence that support the gene-disease association Sum of Genetic & Experimental
Evidence
> 2 pubs w/ convincing evidence over time (>3 yrs)
Assigned Points 12 3.5 15.5 YES
CALCULATED CLASSIFICATION LIMITED 1-6
MODERATE 7-11
STRONG 12-18
DEFINITIVE 12-18 AND replication over time
Valid contradictory evidence (Y/N)*
NO
CALCULATED CLASSIFICATION (DATE)
Definitive
05/14/2020
EXPERT CURATION (DATE)
Definitive
05/14/2020
EVIDENCE SUMMARY
Heterozygous variants in the fumarate hydratase (FH) gene are associated with the autosomal dominant disorder hereditary leiomyomatosis and renal cell cancer (HLRCC). This was first proposed by Tomlinson et al in 2002 (PMID: 11865300). Numerous genetic studies have reported familial segregation of FH variants in families with leiomyomatosis or renal cell cancer. Affected individuals with heterozygous mutations had decreased fumarate hydratase enzyme activity in their lymphoblastoid cell lines although penetrance varies among individuals with similar decreases in FH activity. Tumors from HLRCC patients with a FH germline heterozygous mutations presented markedly reduced enzyme activity due to a second hit on FH, compared with tumors with similar histology from non HLRCC patients. There are substantial other functional assays demonstrating deficiency of FH activity and abnormality in smooth muscle differentiation. In summary, FH is definitively associated with HLRCC. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time.