VCV000041857.38 - ClinVar

NM_144997.7(FLCN):c.268G>T (p.Ala90Ser)

Germline

Classification

criteria provided, conflicting classifications. Learn more about how ClinVar calculates review status.

Conflicting classifications of pathogenicity
Uncertain significance(6); Benign(2); Likely benign(5)

13 out of 17 submissions contributed to this classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_144997.7(FLCN):c.268G>T (p.Ala90Ser)

Variation ID: 41857 Accession: VCV000041857.38

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 17p11.2 17: 17226304 (GRCh38) [ NCBI UCSC ] 17: 17129618 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Apr 12, 2013	Apr 28, 2025	Mar 4, 2025

HGVS

Nucleotide	Protein	Molecular consequence
NM_144997.7:c.268G>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_659434.2:p.Ala90Ser	missense
NM_001353229.2:c.268G>T	NP_001340158.1:p.Ala90Ser	missense
NM_001353230.2:c.268G>T	NP_001340159.1:p.Ala90Ser	missense
NM_001353231.2:c.268G>T	NP_001340160.1:p.Ala90Ser	missense
NM_144606.7:c.268G>T	NP_653207.1:p.Ala90Ser	missense
NM_144997.6:c.268G>T
NC_000017.11:g.17226304C>A
NC_000017.10:g.17129618C>A
NG_008001.2:g.15885G>T
LRG_325:g.15885G>T
LRG_325t1:c.268G>T

... more HGVS ... less HGVS

Protein change

A90S

Other names

Canonical SPDI

NC_000017.11:17226303:C:A

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

The Genome Aggregation Database (gnomAD), exomes 0.00037

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00062

Exome Aggregation Consortium (ExAC) 0.00042

Trans-Omics for Precision Medicine (TOPMed) 0.00021

The Genome Aggregation Database (gnomAD) 0.00029

Links

ClinGen: CA159767 dbSNP: rs141140415 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
FLCN		Sufficient evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	2703	2823

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
not provided	Conflicting classifications of pathogenicity (8)	criteria provided, conflicting classifications	Oct 17, 2023	RCV000034791.27
not specified	Likely benign (2)	criteria provided, single submitter	Mar 4, 2025	RCV000121101.17
Birt-Hogg-Dube syndrome	Benign/Likely benign (2)	criteria provided, multiple submitters, no conflicts	Feb 3, 2025	RCV000227232.27
Familial spontaneous pneumothorax	Uncertain significance (1)	criteria provided, single submitter	Jan 13, 2018	RCV000332283.13
Hereditary cancer-predisposing syndrome	Conflicting classifications of pathogenicity (2)	criteria provided, conflicting classifications	Apr 20, 2021	RCV000571977.15
Birt-Hogg-Dube syndrome 1 Colorectal cancer Familial spontaneous pneumothorax Nonpapillary renal cell carcinoma Potocki-Lupski syndrome	Uncertain significance (1)	criteria provided, single submitter	Jul 30, 2021	RCV005394215.1
Birt-Hogg-Dube syndrome 1	Likely benign (1)	criteria provided, single submitter	Oct 22, 2024	RCV005246599.1

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Uncertain significance (Oct 17, 2023) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Not provided Affected status: unknown Allele origin: germline	Mayo Clinic Laboratories, Mayo Clinic Accession: SCV005412679.1 First in ClinVar: Nov 24, 2024 Last updated: Nov 24, 2024	Number of individuals with the variant: 1
Uncertain significance (Apr 20, 2021) C Contributing to aggregate classification	criteria provided, single submitter (Sema4 Curation Guidelines) Method: curation	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	Sema4, Sema4 Accession: SCV002530133.1 First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022 Comment: The FLCN c.268G>T (p.A90S) variant has been reported in one individual with Birt-Hogg-Dube syndrome, however this individual also carried another variant in FLCN that may … (more) The FLCN c.268G>T (p.A90S) variant has been reported in one individual with Birt-Hogg-Dube syndrome, however this individual also carried another variant in FLCN that may be responsible for disease (PMID: 27734835). It has also been reported in cohorts not ascertained for cancer (PMID: 24728327, 22703879). It was observed in 80/129100 chromosomes of the Non-Finnish European subpopulation, with no homozygotes, in the Genome Aggregation Database (http://gnomad.broadinstitute.org). The variant has been reported in ClinVar (Variation ID 41857). In silico tools suggest the impact of the variant on protein function is inconclusive, though these predictions have not been confirmed by functional studies. The evidence is insufficient to meet ACMG/AMP criteria for classifying the variant as benign or pathogenic. Thus, the clinical significance of this variant is currently uncertain. (less)	Publications: PubMed (3) PubMed: 27734835‚ 24728327‚ 22703879
Likely benign (Aug 31, 2020) C Contributing to aggregate classification	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000321651.8 First in ClinVar: Oct 09, 2016 Last updated: Mar 04, 2023	Comment: This variant is associated with the following publications: (PMID: 24728327, 26096009, 22703879, 27734835)
Uncertain significance (Nov 03, 2021) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: not provided Allele origin: germline	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden Accession: SCV002009876.3 First in ClinVar: Nov 06, 2021 Last updated: Jul 16, 2023
Benign (Nov 17, 2022) C Contributing to aggregate classification	criteria provided, single submitter (Quest Diagnostics criteria) Method: clinical testing	not provided Affected status: unknown Allele origin: unknown	Quest Diagnostics Nichols Institute San Juan Capistrano Accession: SCV004219717.1 First in ClinVar: Jan 06, 2024 Last updated: Jan 06, 2024	Publications: PubMed (3) PubMed: 27734835‚ 24728327‚ 22703879
Uncertain significance (Oct 09, 2023) C Contributing to aggregate classification	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2024) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories Accession: SCV001477789.2 First in ClinVar: Jan 26, 2021 Last updated: Feb 20, 2024	Comment: The FLCN c.268G>T; p.Ala90Ser variant (rs141140415), has not been reported in the medical literature in FLCN-related conditions, but is reported in the ClinVar database (Variation … (more) The FLCN c.268G>T; p.Ala90Ser variant (rs141140415), has not been reported in the medical literature in FLCN-related conditions, but is reported in the ClinVar database (Variation ID: 41857). This variant is found in the general population with an overall allele frequency of 0.03% (97/282,776 alleles) in the Genome Aggregation Database. Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.448). Due to limited information, the clinical significance of this variant is uncertain at this time. (less)
Likely benign (May 09, 2018) C Contributing to aggregate classification	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV000673406.5 First in ClinVar: Jan 01, 2018 Last updated: May 01, 2024	Publications: PubMed (2) PubMed: 24728327‚ 27734835 Comment: This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of … (more) This alteration is classified as likely 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. (less)
Likely benign (Feb 03, 2025) C Contributing to aggregate classification	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Birt-Hogg-Dube syndrome Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000291441.11 First in ClinVar: Jul 01, 2016 Last updated: Feb 25, 2025	Publications: PubMed (1) PubMed: 28492532
Likely benign (Mar 04, 2025) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital Accession: SCV002760908.4 First in ClinVar: Dec 17, 2022 Last updated: Mar 11, 2025	Publications: PubMed (1) PubMed: 27734835
Likely benign (Oct 22, 2024) C Contributing to aggregate classification	criteria provided, single submitter (Myriad Autosomal Dominant, Autosomal Recessive and X-Linked Classification Criteria (2023)) Method: clinical testing	Birt-Hogg-Dube syndrome 1 Affected status: unknown Allele origin: unknown	Myriad Genetics, Inc. Accession: SCV005896327.1 First in ClinVar: Mar 29, 2025 Last updated: Mar 29, 2025	Comment: This variant is considered likely benign. This variant has been observed at a population frequency that is significantly greater than expected given the associated disease … (more) This variant is considered likely benign. This variant has been observed at a population frequency that is significantly greater than expected given the associated disease prevalence and penetrance. (less)
Uncertain significance (Jan 13, 2018) C Contributing to aggregate classification	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Familial spontaneous pneumothorax Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000401023.3 First in ClinVar: Dec 06, 2016 Last updated: May 31, 2020	Comment: This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated … (more) This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. (less)
Benign (Jan 13, 2018) C Contributing to aggregate classification	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Birt-Hogg-Dube syndrome 1 Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000401024.3 First in ClinVar: Dec 06, 2016 Last updated: May 31, 2020	Comment: This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated … (more) This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. (less)
Uncertain significance (Jul 30, 2021) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Colorectal cancer Birt-Hogg-Dube syndrome 1 Nonpapillary renal cell carcinoma Familial spontaneous pneumothorax Potocki-Lupski syndrome Explanation for multiple conditions: Uncertain. The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases. Affected status: unknown Allele origin: germline	Department of Pathology and Laboratory Medicine, Sinai Health System Accession: SCV006057897.1 First in ClinVar: Apr 28, 2025 Last updated: Apr 28, 2025
variant of unknown significance (Jul 13, 2012) N Not contributing to aggregate classification	no assertion criteria provided Method: research	not provided Affected status: no Allele origin: germline	Biesecker Lab/Clinical Genomics Section, National Institutes of Health Study: ClinSeq Accession: SCV000043271.1 First in ClinVar: Apr 12, 2013 Last updated: Apr 12, 2013	Publications: PubMed (1) PubMed: 22703879 Comment: Converted during submission to Uncertain significance. Number of individuals with the variant: 1 Comment on evidence: The study set was not selected for affection status in relation to any cancer. Pathogenicity categories were based on literature curation. See Pubmed ID:22703879 for … (more) The study set was not selected for affection status in relation to any cancer. Pathogenicity categories were based on literature curation. See Pubmed ID:22703879 for details. (less)
Likely benign (-) N Not contributing to aggregate classification	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Genome Diagnostics Laboratory, Amsterdam University Medical Center Study: VKGL Data-share Consensus Accession: SCV001808015.1 First in ClinVar: Aug 26, 2021 Last updated: Aug 26, 2021
Likely benign (-) N Not contributing to aggregate classification	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001954528.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021
not provided (Sep 19, 2013) N Not contributing to aggregate classification	no classification provided Method: reference population	AllHighlyPenetrant Affected status: unknown Allele origin: germline	ITMI Accession: SCV000085269.1 First in ClinVar: Jun 09, 2014 Last updated: Jun 09, 2014 Comment: Please see associated publication for description of ethnicities	Publications: PubMed (1) PubMed: 24728327 Observation 1: Ethnicity/Population group: Whole_cohort Observation 2: Ethnicity/Population group: African Observation 3: Ethnicity/Population group: African_European Observation 4: Ethnicity/Population group: Central_Asian Observation 5: Ethnicity/Population group: East_Asian Observation 6: Ethnicity/Population group: European Observation 7: Ethnicity/Population group: Hispanic
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Comment:

The FLCN c.268G>T; p.Ala90Ser variant (rs141140415), has not been reported in the medical literature in FLCN-related conditions, but is reported in the ClinVar database (Variation ID: 41857). This variant is found in the general population with an overall allele frequency of 0.03% (97/282,776 alleles) in the Genome Aggregation Database. Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.448). Due to limited information, the clinical significance of this variant is uncertain at this time.

Comment:

This alteration is classified as likely 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.

Comment:

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.

Comment:

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Genetic screening of the FLCN gene identify six novel variants and a Danish founder mutation.	Rossing M	Journal of human genetics	2017	PMID: 27734835
Germline variation in cancer-susceptibility genes in a healthy, ancestrally diverse cohort: implications for individual genome sequencing.	Bodian DL	PloS one	2014	PMID: 24728327
Secondary variants in individuals undergoing exome sequencing: screening of 572 individuals identifies high-penetrance mutations in cancer-susceptibility genes.	Johnston JJ	American journal of human genetics	2012	PMID: 22703879

Text-mined citations for rs141140415 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Apr 28, 2025

ClinVar Genomic variation as it relates to human health

NM_144997.7(FLCN):c.268G>T (p.Ala90Ser)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs141140415 ...