NM_000143.4(FH):c.700A>G (p.Thr234Ala) AND Hereditary cancer-predisposing syndrome

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Mar 28, 2023
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000163828.13

Allele description [Variation Report for NM_000143.4(FH):c.700A>G (p.Thr234Ala)]

NM_000143.4(FH):c.700A>G (p.Thr234Ala)

Gene:

FH:fumarate hydratase [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

1q43

Genomic location:

Preferred name:

NM_000143.4(FH):c.700A>G (p.Thr234Ala)

Other names:

p.T234A:ACT>GCT

HGVS:

NC_000001.11:g.241508641T>C
NG_012338.1:g.16114A>G
NM_000143.4:c.700A>GMANE SELECT
NP_000134.2:p.Thr234Ala
NP_000134.2:p.Thr234Ala
LRG_504t1:c.700A>G
LRG_504:g.16114A>G
LRG_504p1:p.Thr234Ala
NC_000001.10:g.241671941T>C
NM_000143.3:c.700A>G
p.T234A

Protein change:

T234A

Links:

dbSNP: rs372505976

NCBI 1000 Genomes Browser:

rs372505976

Molecular consequence:

NM_000143.4:c.700A>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Hereditary cancer-predisposing syndrome
Synonyms:: Neoplastic Syndromes, Hereditary; Tumor predisposition; Cancer predisposition; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0015356; MeSH: D009386; MedGen: C0027672

Recent activity

Clear Turn Off Turn On

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

Help

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000214414	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Pathogenic (Mar 28, 2023)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 24334767, 25004247, 30050099, 35993574, 36773955 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000214414

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Pathogenic
(Mar 28, 2023)

germline

clinical testing

PubMed (5)
[See all records that cite these PMIDs]

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Germline mutations in FH confer predisposition to malignant pheochromocytomas and paragangliomas.

Castro-Vega LJ, Buffet A, De Cubas AA, Cascón A, Menara M, Khalifa E, Amar L, Azriel S, Bourdeau I, Chabre O, Currás-Freixes M, Franco-Vidal V, Guillaud-Bataille M, Simian C, Morin A, Letón R, Gómez-Graña A, Pollard PJ, Rustin P, Robledo M, Favier J, Gimenez-Roqueplo AP.

Hum Mol Genet. 2014 May 1;23(9):2440-6. doi: 10.1093/hmg/ddt639. Epub 2013 Dec 13.

PubMed [citation]

PMID:: 24334767

Germline FH mutations presenting with pheochromocytoma.

Clark GR, Sciacovelli M, Gaude E, Walsh DM, Kirby G, Simpson MA, Trembath RC, Berg JN, Woodward ER, Kinning E, Morrison PJ, Frezza C, Maher ER.

J Clin Endocrinol Metab. 2014 Oct;99(10):E2046-50. doi: 10.1210/jc.2014-1659. Epub 2014 Jul 8.

PubMed [citation]

PMID:: 25004247

See all PubMed Citations (5)

Details of each submission

From Ambry Genetics, SCV000214414.8

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

The p.T234A variant (also known as c.700A>G), located in coding exon 5 of the FH gene, results from an A to G substitution at nucleotide position 700. The threonine at codon 234 is replaced by alanine, an amino acid with similar properties. This alteration has been identified in numerous patients with a personal and/or family history of pheochromocytomas or paragangliomas, including tumors with a loss of fumarate hydratase staining in immunohistochemistry experiments (Ambry internal data; Richter S et al. Genet. Med. 2018 Jul; Fuchs TL et al. Am J Surg Pathol 2023 Jan;47(1):25-36; Zavoshi S et al. Urology 2023 Feb.). Based on internal structural analysis, this amino acid sits at the interface of two monomer subunits and this substitution is anticipated to result in a significant decrease in structural stability (Baugh L et al. Tuberculosis (Edinb). 2015 Mar;95:142-8; Ambry internal data). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation in association with PPGL, however its association with other features of hereditary leiomyomatosis and renal cell carcinoma syndrome is unclear.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Nov 3, 2024

ClinVar

Relating variation to medicine