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NM_000143.4(FH):c.935T>C (p.Phe312Ser) AND Hereditary cancer-predisposing syndrome

Germline classification:
Pathogenic (1 submission)
Last evaluated:
Jul 8, 2021
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:
RCV002445265.9

Allele description [Variation Report for NM_000143.4(FH):c.935T>C (p.Phe312Ser)]

NM_000143.4(FH):c.935T>C (p.Phe312Ser)

Gene:
FH:fumarate hydratase [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
1q43
Genomic location:
Preferred name:
NM_000143.4(FH):c.935T>C (p.Phe312Ser)
HGVS:
  • NC_000001.11:g.241504215A>G
  • NG_012338.1:g.20540T>C
  • NM_000143.4:c.935T>CMANE SELECT
  • NP_000134.2:p.Phe312Ser
  • LRG_504t1:c.935T>C
  • LRG_504:g.20540T>C
  • NC_000001.10:g.241667515A>G
  • NM_000143.3:c.935T>C
Protein change:
F312S
Links:
dbSNP: rs1553341046
NCBI 1000 Genomes Browser:
rs1553341046
Molecular consequence:
  • NM_000143.4:c.935T>C - 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

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Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV002682338Ambry Genetics
criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)		Pathogenic
(Jul 8, 2021) 		germlineclinical testing

PubMed (1)
[See all records that cite this PMID]

Citation Link

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Summary from all submissions

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

Citations

PubMed

Novel FH mutations in families with hereditary leiomyomatosis and renal cell cancer (HLRCC) and patients with isolated type 2 papillary renal cell carcinoma.

Gardie B, Remenieras A, Kattygnarath D, Bombled J, Lefèvre S, Perrier-Trudova V, Rustin P, Barrois M, Slama A, Avril MF, Bessis D, Caron O, Caux F, Collignon P, Coupier I, Cremin C, Dollfus H, Dugast C, Escudier B, Faivre L, Field M, Gilbert-Dussardier B, et al.

J Med Genet. 2011 Apr;48(4):226-34. doi: 10.1136/jmg.2010.085068. Epub 2011 Mar 12. Erratum in: J Med Genet. 2011 Aug;48(8):576.

PubMed [citation]
PMID:
21398687

Details of each submission

From Ambry Genetics, SCV002682338.2

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

Description

The p.F312S pathogenic mutation (also known as c.935T>C), located in coding exon 7 of the FH gene, results from a T to C substitution at nucleotide position 935. The phenylalanine at codon 312 is replaced by serine, an amino acid with highly dissimilar properties. Another alteration at the same codon, p.F312L (c.934T>C), co-segregated with disease in 4/4 individuals from one family tested in our laboratory (Ambry internal data). The p.F312S alteration has been observed in at least one individual with a personal and/or family history that is consistent with HLRCC-related disease (Ambry internal data). This variant (previously designated as p.Phe269Ser) has also been identified in the literature in an individual with suspected HLRCC; FH activity from lymphoblastoid cell lines from this individual was 36% compared to wildtype (Gardie B et al. J Med Genet, 2011 Apr;48:226-34). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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.

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

Last Updated: Sep 29, 2024