NM_144997.7(FLCN):c.553T>C (p.Ser185Pro) AND Birt-Hogg-Dube syndrome

Germline classification:: Conflicting interpretations of pathogenicity (2 submissions)
Last evaluated:: Apr 30, 2022
Review status:: criteria provided, conflicting classifications

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:: RCV000222633.8

Allele description [Variation Report for NM_144997.7(FLCN):c.553T>C (p.Ser185Pro)]

NM_144997.7(FLCN):c.553T>C (p.Ser185Pro)

Gene:

FLCN:folliculin [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

17p11.2

Genomic location:

Preferred name:

NM_144997.7(FLCN):c.553T>C (p.Ser185Pro)

HGVS:

NC_000017.11:g.17223987A>G
NG_008001.2:g.18202T>C
NM_001353229.2:c.607T>C
NM_001353230.2:c.553T>C
NM_001353231.2:c.553T>C
NM_144606.7:c.553T>C
NM_144997.7:c.553T>CMANE SELECT
NP_001340158.1:p.Ser203Pro
NP_001340159.1:p.Ser185Pro
NP_001340160.1:p.Ser185Pro
NP_653207.1:p.Ser185Pro
NP_659434.2:p.Ser185Pro
LRG_325t1:c.553T>C
LRG_325:g.18202T>C
NC_000017.10:g.17127301A>G
NM_144997.5:c.553T>C

Protein change:

S185P

Links:

dbSNP: rs876657646

NCBI 1000 Genomes Browser:

rs876657646

Molecular consequence:

NM_001353229.2:c.607T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001353230.2:c.553T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001353231.2:c.553T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_144606.7:c.553T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_144997.7:c.553T>C - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Name:: Birt-Hogg-Dube syndrome
Synonyms:: BHD syndrome; Birt Hogg Dubé syndrome
Identifiers:: MONDO: MONDO:0800444; MedGen: C0346010; Orphanet: 122; OMIM: PS135150

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000271225	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (LMM Criteria)	Likely pathogenic (Feb 6, 2017)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 23414156, 24033266
SCV003441677	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Apr 30, 2022)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 23414156, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000271225

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

criteria provided, single submitter

(LMM Criteria)

Likely pathogenic
(Feb 6, 2017)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

SCV003441677

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Apr 30, 2022)

germline

clinical testing

PubMed (2)
[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	not provided	2	1	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

A systematic approach to assessing the clinical significance of genetic variants.

Duzkale H, Shen J, McLaughlin H, Alfares A, Kelly MA, Pugh TJ, Funke BH, Rehm HL, Lebo MS.

Clin Genet. 2013 Nov;84(5):453-63. doi: 10.1111/cge.12257.

PubMed [citation]

PMID:: 24033266
PMCID:: PMC3995020

Birt-Hogg-Dubé syndrome in a patient with melanoma and a novel mutation in the FCLN gene.

Mota-Burgos A, Acosta EH, Márquez FV, Mendiola M, Herrera-Ceballos E.

Int J Dermatol. 2013 Mar;52(3):323-6. doi: 10.1111/j.1365-4632.2012.05742.x.

PubMed [citation]

PMID:: 23414156

See all PubMed Citations (3)

Details of each submission

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV000271225.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	2	not provided	not provided	clinical testing	PubMed (2)

Description

The p.Ser185Pro variant in FLCN has been reported in 1 individual with Birt Hogg Dube syndrome (BHDS), segregated with disease in 2 affected relatives (Mota-Bur gos 2013, LMM unpublished data), and was absent from large population studies. F LCN is the only gene known to be associated with BHDS and a disease causing vari ant is present in ~90% of patients. Other supporting evidence includes a strong evolutionary conservation of the affected amino acid, suggesting that a change w ould not be tolerated. In summary, although additional studies are required to f ully establish its clinical significance, the p.Ser185Pro variant is likely path ogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		2	not provided	1	not provided

From Invitae, SCV003441677.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 228263). This missense change has been observed in individuals with Birt-Hogg-Dube¬¥ syndrome (PMID: 23414156; Invitae). This sequence change replaces serine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 185 of the FLCN protein (p.Ser185Pro). This variant is not present in population databases (gnomAD no frequency).

#	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: Mar 30, 2024

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