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NM_000143.4(FH):c.1093A>G (p.Ser365Gly) AND Hereditary cancer-predisposing syndrome

Germline classification:
Pathogenic (1 submission)
Last evaluated:
Nov 30, 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:
RCV000220270.13

Allele description [Variation Report for NM_000143.4(FH):c.1093A>G (p.Ser365Gly)]

NM_000143.4(FH):c.1093A>G (p.Ser365Gly)

Gene:
FH:fumarate hydratase [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
1q43
Genomic location:
Preferred name:
NM_000143.4(FH):c.1093A>G (p.Ser365Gly)
Other names:
p.S365G:AGC>GGC
HGVS:
  • NC_000001.11:g.241504057T>C
  • NG_012338.1:g.20698A>G
  • NM_000143.4:c.1093A>GMANE SELECT
  • NP_000134.2:p.Ser365Gly
  • NP_000134.2:p.Ser365Gly
  • LRG_504t1:c.1093A>G
  • LRG_504:g.20698A>G
  • LRG_504p1:p.Ser365Gly
  • NC_000001.10:g.241667357T>C
  • NM_000143.3:c.1093A>G
  • p.[Ser365Gly]
Protein change:
S365G
Links:
dbSNP: rs863223966
NCBI 1000 Genomes Browser:
rs863223966
Molecular consequence:
  • NM_000143.4:c.1093A>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

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV000278463Ambry Genetics
criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)		Pathogenic
(Nov 30, 2023) 		germlineclinical testing

PubMed (7)
[See all records that cite these PMIDs]

Citation Link

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Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Mutations in the fumarate hydratase gene cause hereditary leiomyomatosis and renal cell cancer in families in North America.

Toro JR, Nickerson ML, Wei MH, Warren MB, Glenn GM, Turner ML, Stewart L, Duray P, Tourre O, Sharma N, Choyke P, Stratton P, Merino M, Walther MM, Linehan WM, Schmidt LS, Zbar B.

Am J Hum Genet. 2003 Jul;73(1):95-106. Epub 2003 May 22.

PubMed [citation]
PMID:
12772087
PMCID:
PMC1180594

Novel mutations in FH and expansion of the spectrum of phenotypes expressed in families with hereditary leiomyomatosis and renal cell cancer.

Wei MH, Toure O, Glenn GM, Pithukpakorn M, Neckers L, Stolle C, Choyke P, Grubb R, Middelton L, Turner ML, Walther MM, Merino MJ, Zbar B, Linehan WM, Toro JR.

J Med Genet. 2006 Jan;43(1):18-27. Epub 2005 Jun 3.

PubMed [citation]
PMID:
15937070
PMCID:
PMC2564499
See all PubMed Citations (7)

Details of each submission

From Ambry Genetics, SCV000278463.8

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (7)

Description

The p.S365G pathogenic mutation (also known as c.1093A>G), located in coding exon 7 of the FH gene, results from an A to G substitution at nucleotide position 1093. The serine at codon 365 is replaced by glycine, an amino acid with similar properties. This alteration (referred to as p.S322G) has been reported in multiple individuals diagnosed with hereditary leiomyomatosis and renal cell carcinoma (HLRCC) (Toro J et al. Am J Hum Genet. 2003 Jul;73(1):95-106; Wei M et al. J Med Genet. 2006 Jan;43(1):18-27). In addition, this variant is located within the gene active site, a region where mutations have been known to cluster and are predicted to affect the activity of the FH protein (Picaud S et al. J Inherit Metab Dis. 2011 Jun;34(3):671-6; Pithukpakorn M et al. J Med Genet. 2006 Sep;43(9):755-62). 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 internal structural analysis, this variant disrupts a specific protein-ligand interaction involved with fumarate-binding and protein function (Ambry internal data; Pereira de Pádua RA et al. Acta Crystallogr F Struct Biol Commun. 2014 Jan;70:120-2; Mechaly AE et al. FEBS Lett. 2012 Jun;586:1606-11). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Oct 26, 2024