NM_144997.7(FLCN):c.1387T>C (p.Tyr463His) AND Hereditary cancer-predisposing syndrome

Germline classification:: Conflicting interpretations of pathogenicity (2 submissions)
Last evaluated:: Apr 13, 2023
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:: RCV000561721.7

Allele description [Variation Report for NM_144997.7(FLCN):c.1387T>C (p.Tyr463His)]

NM_144997.7(FLCN):c.1387T>C (p.Tyr463His)

Gene:

FLCN:folliculin [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

17p11.2

Genomic location:

Preferred name:

NM_144997.7(FLCN):c.1387T>C (p.Tyr463His)

HGVS:

NC_000017.11:g.17215230A>G
NG_008001.2:g.26959T>C
NM_001353229.2:c.1441T>C
NM_001353230.2:c.1387T>C
NM_001353231.2:c.1387T>C
NM_144997.6:c.1387T>C
NM_144997.7:c.1387T>CMANE SELECT
NP_001340158.1:p.Tyr481His
NP_001340159.1:p.Tyr463His
NP_001340160.1:p.Tyr463His
NP_659434.2:p.Tyr463His
LRG_325t1:c.1387T>C
LRG_325:g.26959T>C
NC_000017.10:g.17118544A>G
NM_144997.5:c.1387T>C

Protein change:

Y463H

Links:

dbSNP: rs770077517

NCBI 1000 Genomes Browser:

rs770077517

Molecular consequence:

NM_001353229.2:c.1441T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001353230.2:c.1387T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001353231.2:c.1387T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_144997.7:c.1387T>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
SCV000673430	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Benign (Apr 13, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 26580448, 28202063, 31615547 Citation Link,
SCV002530117	Sema4, Sema4	criteria provided, single submitter (Sema4 Curation Guidelines)	Uncertain significance (Aug 17, 2021)	germline	curation	PubMed (2) [See all records that cite these PMIDs] 28202063, 26580448 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000673430

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Benign
(Apr 13, 2023)

germline

clinical testing

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

Citation Link,

SCV002530117

Sema4, Sema4

criteria provided, single submitter

(Sema4 Curation Guidelines)

Uncertain significance
(Aug 17, 2021)

germline

curation

PubMed (2)
[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, curation

Citations

PubMed

Genotypic characteristics of Chinese patients with BHD syndrome and functional analysis of FLCN variants.

Liu K, Xu W, Tian X, Xiao M, Zhao X, Zhang Q, Qu T, Song J, Liu Y, Xu KF, Zhang X.

Orphanet J Rare Dis. 2019 Oct 15;14(1):223. doi: 10.1186/s13023-019-1198-y.

PubMed [citation]

PMID:: 31615547
PMCID:: PMC6794894

Next-generation sequencing in familial breast cancer patients from Lebanon.

Jalkh N, Chouery E, Haidar Z, Khater C, Atallah D, Ali H, Marafie MJ, Al-Mulla MR, Al-Mulla F, Megarbane A.

BMC Med Genomics. 2017 Feb 15;10(1):8. doi: 10.1186/s12920-017-0244-7.

PubMed [citation]

PMID:: 28202063
PMCID:: PMC5312584

See all PubMed Citations (3)

Details of each submission

From Ambry Genetics, SCV000673430.6

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

Description

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

#	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 Sema4, Sema4, SCV002530117.1

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

#	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: Oct 13, 2024

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