NM_000143.4(FH):c.1093A>G (p.Ser365Gly) AND Hereditary leiomyomatosis and renal cell cancer

Germline classification:: Pathogenic/Likely pathogenic (3 submissions)
Last evaluated:: Jan 17, 2024
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV000445606.11

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]

Observations:

Condition(s)

Name:: Hereditary leiomyomatosis and renal cell cancer
Synonyms:: Reed syndrome; Multiple cutaneous and uterine leiomyomatosis; Cutaneous leiomyomata with uterine leiomyomata; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0007888; MedGen: C1708350; Orphanet: 523; OMIM: 150800; Human Phenotype Ontology: HP:0007437

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000537257	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	criteria provided, single submitter (DGD Variant Analysis Guidelines)	Pathogenic (Jan 17, 2017)	germline	clinical testing	DGD_Variant_Analysis_Guidelines.docx, Citation Link,
SCV004038341	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Aug 1, 2023)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 15937070, 12772087, 28300276, 33789101, 22565324, 22243733 Citation Link,
SCV004933677	Myriad Genetics, Inc.	criteria provided, single submitter (Myriad Autosomal Dominant, Autosomal Recessive and X-Linked Classification Criteria (2023))	Likely pathogenic (Jan 17, 2024)	unknown	clinical testing	PubMed (5) [See all records that cite these PMIDs] 22565324, 12772087, 15937070, 28300276, 33789101 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000537257

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

criteria provided, single submitter

(DGD Variant Analysis Guidelines)

Pathogenic
(Jan 17, 2017)

germline

clinical testing

DGD_Variant_Analysis_Guidelines.docx,

Citation Link,

SCV004038341

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Pathogenic
(Aug 1, 2023)

germline

clinical testing

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

Citation Link,

SCV004933677

Myriad Genetics, Inc.

criteria provided, single submitter

(Myriad Autosomal Dominant, Autosomal Recessive and X-Linked Classification Criteria (2023))

Likely pathogenic
(Jan 17, 2024)

unknown

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	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	yes	5	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

JAAD Grand Rounds quiz. A 46-year-old man with agminated papules on the buttock. Reed syndrome.

Mitchum MD, Adams EG, Holcomb KZ.

J Am Acad Dermatol. 2012 Feb;66(2):337-9. doi: 10.1016/j.jaad.2010.04.013. No abstract available.

PubMed [citation]

PMID:: 22243733

Bilateral ovarian steroid cell tumours and massive macronodular adrenocortical disease in a patient with hereditary leiomyomatosis and renal cell cancer syndrome.

Arora R, Eble JN, Pierce HH, Crispen PL, DeSimone CP, Lee EY, Karabakhtsian RG.

Pathology. 2012 Jun;44(4):360-3. doi: 10.1097/PAT.0b013e328353bf5a. No abstract available.

PubMed [citation]

PMID:: 22565324

See all PubMed Citations (6)

Details of each submission

From Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia, SCV000537257.1

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

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		5	not provided	not provided	not provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV004038341.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

Variant summary: FH c.1093A>G (p.Ser365Gly) results in a non-conservative amino acid change located in the Fumarate lyase, N-terminal domain (IPR022761) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251080 control chromosomes (gnomAD). c.1093A>G has been reported in the literature in multiple individuals affected with Hereditary Leiomyomatosis And Renal Cell Cancer (examples: Toro_2003, Wei_2006, Mitchum_2012, Arora_2012, Muller_2017, Abou_2021). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 33789101, 22565324, 12772087, 15937070, 28300276, 22243733 ). Different variant affecting the same codon has been classified pathogenic in ClinVar (c.1094G>A /p.Ser365Asn, CV ID 429174 ). Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was 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

From Myriad Genetics, Inc., SCV004933677.1

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

Description

This variant is considered likely pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 22565324, 12772087, 15937070, 28300276, 33789101]. This variant is expected to disrupt protein structure [Myriad internal data].

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

Last Updated: Oct 26, 2024

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