NM_144997.7(FLCN):c.1387T>C (p.Tyr463His) AND not provided

Germline classification:: Conflicting interpretations of pathogenicity (3 submissions)
Last evaluated:: Apr 18, 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:: RCV001354212.5

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)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001548768	Department of Pathology and Laboratory Medicine, Sinai Health System - The Canadian Open Genetics Repository (COGR) See additional submitters Franklin by Genoox	no assertion criteria provided	Uncertain significance	unknown	clinical testing
SCV001764608	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Likely benign (Jul 5, 2019)	germline	clinical testing	Citation Link,
SCV004218928	Quest Diagnostics Nichols Institute San Juan Capistrano	criteria provided, single submitter (Quest Diagnostics criteria)	Uncertain significance (Apr 18, 2023)	unknown	clinical testing	PubMed (3) [See all records that cite these PMIDs] 28202063, 26580448, 26467025

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001548768

Department of Pathology and Laboratory Medicine, Sinai Health System - The Canadian Open Genetics Repository (COGR)

See additional submitters

no assertion criteria provided

Uncertain significance

unknown

clinical testing

SCV001764608

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Likely benign
(Jul 5, 2019)

germline

clinical testing

Citation Link,

SCV004218928

Quest Diagnostics Nichols Institute San Juan Capistrano

criteria provided, single submitter

(Quest Diagnostics criteria)

Uncertain significance
(Apr 18, 2023)

unknown

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

Citations

PubMed

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

Germline Mutations in Predisposition Genes in Pediatric Cancer.

Zhang J, Walsh MF, Wu G, Edmonson MN, Gruber TA, Easton J, Hedges D, Ma X, Zhou X, Yergeau DA, Wilkinson MR, Vadodaria B, Chen X, McGee RB, Hines-Dowell S, Nuccio R, Quinn E, Shurtleff SA, Rusch M, Patel A, Becksfort JB, Wang S, et al.

N Engl J Med. 2015 Dec 10;373(24):2336-2346. doi: 10.1056/NEJMoa1508054. Epub 2015 Nov 18.

PubMed [citation]

PMID:: 26580448
PMCID:: PMC4734119

See all PubMed Citations (3)

Details of each submission

From Department of Pathology and Laboratory Medicine, Sinai Health System - The Canadian Open Genetics Repository (COGR), SCV001548768.1

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

Description

The FLCN p.Tyr463His variant was not identified in the literature nor was it identified in Cosmic or LOVD 3.0. The variant was identified in dbSNP (ID: rs770077517) and ClinVar (classified as a VUS by Invitae and Ambry Genetics). The variant was also identified in control databases in 13 of 282816 chromosomes at a frequency of 0.00004597 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: Latino in 7 of 35438 chromosomes (freq: 0.000198) and European (non-Finnish) in 6 of 129160 chromosomes (freq: 0.000046), but was not observed in the African, Ashkenazi Jewish, East Asian, European (Finnish), Other or South Asian populations. The p.Tyr463 residue is conserved in mammals but not in more distantly related organisms however four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and four of four in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing. However, this information is not predictive enough to assume pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.

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

From GeneDx, SCV001764608.1

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

Description

In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 28202063)

#	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		not provided	not provided	not provided	not provided

From Quest Diagnostics Nichols Institute San Juan Capistrano, SCV004218928.1

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

Description

In the published literature, the variant has been reported in individuals with breast cancer (PMID: 28202063 (2017)) and acute lymphoblastic leukemia (ALL) (PMID: 26580448 (2015)). The frequency of this variant in the general population, 0.0002 (7/35438 chromosomes in Latino/Admixed American subpopulation, http://gnomad.broadinstitute.org), is higher than would generally be expected for pathogenic variants in this gene. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant.

#	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 13, 2024

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