NM_144997.7(FLCN):c.1657T>C (p.Trp553Arg) AND Hereditary cancer-predisposing syndrome

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Dec 13, 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:: RCV000492176.4

Allele description [Variation Report for NM_144997.7(FLCN):c.1657T>C (p.Trp553Arg)]

NM_144997.7(FLCN):c.1657T>C (p.Trp553Arg)

Gene:

FLCN:folliculin [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

17p11.2

Genomic location:

Preferred name:

NM_144997.7(FLCN):c.1657T>C (p.Trp553Arg)

HGVS:

NC_000017.11:g.17213738A>G
NG_008001.2:g.28451T>C
NM_001353229.2:c.1711T>C
NM_001353230.2:c.1657T>C
NM_001353231.2:c.1657T>C
NM_144997.7:c.1657T>CMANE SELECT
NP_001340158.1:p.Trp571Arg
NP_001340159.1:p.Trp553Arg
NP_001340160.1:p.Trp553Arg
NP_659434.2:p.Trp553Arg
LRG_325t1:c.1657T>C
LRG_325:g.28451T>C
NC_000017.10:g.17117052A>G
NM_144997.5:c.1657T>C

Protein change:

W553R

Links:

dbSNP: rs1131690833

NCBI 1000 Genomes Browser:

rs1131690833

Molecular consequence:

NM_001353229.2:c.1711T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001353230.2:c.1657T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001353231.2:c.1657T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_144997.7:c.1657T>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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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000580742	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Likely pathogenic (Dec 13, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 22977732, 27355777, 28970150 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000580742

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Likely pathogenic
(Dec 13, 2023)

germline

clinical testing

PubMed (3)
[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	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Crystal structure of folliculin reveals a hidDENN function in genetically inherited renal cancer.

Nookala RK, Langemeyer L, Pacitto A, Ochoa-Montaño B, Donaldson JC, Blaszczyk BK, Chirgadze DY, Barr FA, Bazan JF, Blundell TL.

Open Biol. 2012 Aug;2(8):120071. doi: 10.1098/rsob.120071.

PubMed [citation]

PMID:: 22977732
PMCID:: PMC3438538

Folliculin - A tumor suppressor at the intersection of metabolic signaling and membrane traffic.

Dodding MP.

Small GTPases. 2017 Apr 3;8(2):100-105. doi: 10.1080/21541248.2016.1204808. Epub 2016 Jun 29. Review.

PubMed [citation]

PMID:: 27355777
PMCID:: PMC5464117

See all PubMed Citations (3)

Details of each submission

From Ambry Genetics, SCV000580742.6

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

Description

The p.W553R variant (also known as c.1657T>C), located in coding exon 11 of the FLCN gene, results from a T to C substitution at nucleotide position 1657. The tryptophan at codon 553 is replaced by arginine, an amino acid with dissimilar properties. This alteration has been observed in multiple individuals with a personal or family history that is consistent with FLCN-associated disease (Ambry internal data). Based on internal structural assessment, this alteration disrupts the C-terminal DENN-like domain, which is a guanine nucleotide exchange factor implicated in FLCN’s role in membrane trafficking (Ambry internal data; Nookala RK et al. Open Biol, 2012 Aug;2:120071; Dodding MP. Small GTPases, 2017 04;8:100-105; Schmidt LS et al. Gene, 2018 Jan;640:28-42). This amino acid position is highly conserved in available vertebrate species. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be 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 3, 2024

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