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NM_000143.4(FH):c.1097G>A (p.Ser366Asn) AND Hereditary cancer-predisposing syndrome

Germline classification:
Pathogenic (1 submission)
Last evaluated:
May 23, 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:
RCV001017278.13

Allele description [Variation Report for NM_000143.4(FH):c.1097G>A (p.Ser366Asn)]

NM_000143.4(FH):c.1097G>A (p.Ser366Asn)

Gene:
FH:fumarate hydratase [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
1q43
Genomic location:
Preferred name:
NM_000143.4(FH):c.1097G>A (p.Ser366Asn)
Other names:
p.S366N:AGT>AAT
HGVS:
  • NC_000001.11:g.241504053C>T
  • NG_012338.1:g.20702G>A
  • NM_000143.4:c.1097G>AMANE SELECT
  • NP_000134.2:p.Ser366Asn
  • NP_000134.2:p.Ser366Asn
  • LRG_504t1:c.1097G>A
  • LRG_504:g.20702G>A
  • LRG_504p1:p.Ser366Asn
  • NC_000001.10:g.241667353C>T
  • NM_000143.3:c.1097G>A
Protein change:
S366N
Links:
dbSNP: rs863224004
NCBI 1000 Genomes Browser:
rs863224004
Molecular consequence:
  • NM_000143.4:c.1097G>A - 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

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV001178332Ambry Genetics
criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)
Pathogenic
(May 23, 2023)
germlineclinical testing

PubMed (6)
[See all records that cite these PMIDs]

Citation Link

Summary from all submissions

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

Citations

PubMed

Genetic and functional analyses of FH mutations in multiple cutaneous and uterine leiomyomatosis, hereditary leiomyomatosis and renal cancer, and fumarate hydratase deficiency.

Alam NA, Rowan AJ, Wortham NC, Pollard PJ, Mitchell M, Tyrer JP, Barclay E, Calonje E, Manek S, Adams SJ, Bowers PW, Burrows NP, Charles-Holmes R, Cook LJ, Daly BM, Ford GP, Fuller LC, Hadfield-Jones SE, Hardwick N, Highet AS, Keefe M, MacDonald-Hull SP, et al.

Hum Mol Genet. 2003 Jun 1;12(11):1241-52.

PubMed [citation]
PMID:
12761039

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
See all PubMed Citations (6)

Details of each submission

From Ambry Genetics, SCV001178332.6

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (6)

Description

The p.S366N pathogenic mutation (also known as c.1097G>A), located in coding exon 7 of the FH gene, results from a G to A substitution at nucleotide position 1097. The serine at codon 366 is replaced by asparagine, an amino acid with highly similar properties. This alteration has been reported in numerous individuals with multiple cutaneous and uterine leiyomyomatosis (Alam NA et al. J Mol Diagn. 2005 Oct;7:437-43; Toro JR et al. Am. J. Hum. Genet. 2003 Jul;73:95-106; Bardella C et al. J. Pathol. 2011 Sep;225(1):4-11; Gupta S et al. Hum Pathol, 2019 Sep;91:114-122; Ambry internal data). Immunohistochemical analysis of tumors in patients with the germline p.S366N mutation have shown that this alteration results in an accumulation of succinated proteins as a result of deficient fumarase; these patients' tumors also demonstrated loss of heterozygosity (Bardella C et al. J. Pathol. 2011 Sep;225(1):4-11). In addition, the p.S366N variant has been predicted to alter the enzymatic active site of the FH protein (Picaud S et al. J. Inherit. Metab. Dis. 2011 Jun;34:671-6; Alam NA et al. Hum. Mol. Genet. 2003 Jun;12:1241-52). Based on internal structural analysis, this variant is anticipated to disrupt a region of known function (Ajalla Aleixo MA et al. FEBS J. 2019 May;286:1925-1940; Mechaly AE et al. FEBS Lett. 2012 Jun;586:1606-11). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Of note, this alteration is also designated as S323N (c.968G>A) in some published literature. 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