NM_000143.4(FH):c.557G>A (p.Ser186Asn) AND not provided

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Oct 3, 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:: RCV002514749.10

Allele description [Variation Report for NM_000143.4(FH):c.557G>A (p.Ser186Asn)]

NM_000143.4(FH):c.557G>A (p.Ser186Asn)

Gene:

FH:fumarate hydratase [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

1q43

Genomic location:

Preferred name:

NM_000143.4(FH):c.557G>A (p.Ser186Asn)

HGVS:

NC_000001.11:g.241508784C>T
NG_012338.1:g.15971G>A
NM_000143.4:c.557G>AMANE SELECT
NP_000134.2:p.Ser186Asn
NP_000134.2:p.Ser186Asn
LRG_504t1:c.557G>A
LRG_504:g.15971G>A
LRG_504p1:p.Ser186Asn
NC_000001.10:g.241672084C>T
NM_000143.3:c.557G>A
p.S186N

Protein change:

S186N

Links:

dbSNP: rs587782618

NCBI 1000 Genomes Browser:

rs587782618

Molecular consequence:

NM_000143.4:c.557G>A - missense variant - [Sequence Ontology: SO:0001583]

Functional consequence:

Decreased function

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001221688	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Oct 3, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 31444830, 35163394, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001221688

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Oct 3, 2023)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

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

Fumarate hydratase FH c.1431_1433dupAAA (p.Lys477dup) variant is not associated with cancer including renal cell carcinoma.

Zhang L, Walsh MF, Jairam S, Mandelker D, Zhong Y, Kemel Y, Chen YB, Musheyev D, Zehir A, Jayakumaran G, Brzostowski E, Birsoy O, Yang C, Li Y, Somar J, DeLair D, Pradhan N, Berger MF, Cadoo K, Carlo MI, Robson ME, Stadler ZK, et al.

Hum Mutat. 2020 Jan;41(1):103-109. doi: 10.1002/humu.23900. Epub 2019 Sep 3.

PubMed [citation]

PMID:: 31444830
PMCID:: PMC6930334

Functional Characterization of FH Mutation c.557G>A Underlies Uterine Leiomyomas.

Li P, Wu Y, Wu H, Xiong Q, Zhao N, Chen G, Wu C, Xiao H.

Int J Mol Sci. 2022 Jan 27;23(3). doi: 10.3390/ijms23031452.

PubMed [citation]

PMID:: 35163394
PMCID:: PMC8836152

See all PubMed Citations (3)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001221688.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

This sequence change replaces serine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 186 of the FH protein (p.Ser186Asn). This variant is present in population databases (rs587782618, gnomAD 0.01%). This missense change has been observed in individual(s) with clinical features of hereditary leiomyomatosis and renal cell cancer (PMID: 31444830, 35163394; external communication). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 142654). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects FH function (PMID: 35163394). For these reasons, this variant has been classified as Pathogenic.

#	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 24, 2024

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