VCV000134280.13 - ClinVar

NM_000135.4(FANCA):c.4015C>T (p.Leu1339Phe)

Germline

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.

(10)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Conflicting classifications of pathogenicity
Uncertain significance(6); Likely benign(1)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000135.4(FANCA):c.4015C>T (p.Leu1339Phe)

Variation ID: 134280 Accession: VCV000134280.13

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 16q24.3 16: 89739285 (GRCh38) [ NCBI UCSC ] 16: 89805693 (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	Jun 9, 2014	Oct 8, 2024	Jan 29, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000135.4:c.4015C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000126.2:p.Leu1339Phe	missense
NM_001113525.2:c.*1039G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.		3 prime UTR
NM_000135.3:c.4015C>T
NM_001286167.3:c.4015C>T	NP_001273096.1:p.Leu1339Phe	missense
NM_152287.4:c.*1039G>A		3 prime UTR
NR_110122.2:n.3039G>A		non-coding transcript variant
NR_110126.2:n.2922G>A		non-coding transcript variant
NR_110128.2:n.2862G>A		non-coding transcript variant
NR_110129.2:n.2956G>A		non-coding transcript variant
NC_000016.10:g.89739285G>A
NC_000016.9:g.89805693G>A
NG_011706.1:g.82373C>T
LRG_495:g.82373C>T
LRG_495t1:c.4015C>T	LRG_495p1:p.Leu1339Phe

... more HGVS ... less HGVS

Protein change

L1339F

Other names

p.Leu1339Phe

Canonical SPDI

NC_000016.10:89739284:G: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.

0.00060 (A)

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

The Genome Aggregation Database (gnomAD) 0.00015

Trans-Omics for Precision Medicine (TOPMed) 0.00022

1000 Genomes Project 0.00060

1000 Genomes Project 30x 0.00062

Exome Aggregation Consortium (ExAC) 0.00004

The Genome Aggregation Database (gnomAD), exomes 0.00005

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008

Links

ClinGen: CA159343 dbSNP: rs149775657 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.
FANCA		-	-	GRCh38 GRCh37	4166	5324
ZNF276		-	-	GRCh38 GRCh37	52	878

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 specified	not provided (1)	no classification provided	Sep 19, 2013	RCV000120953.1
Fanconi anemia complementation group A	Uncertain significance (4)	criteria provided, multiple submitters, no conflicts	Nov 26, 2019	RCV000666660.6
Fanconi anemia	Conflicting interpretations of pathogenicity (2)	criteria provided, conflicting classifications	Jan 29, 2024	RCV000824570.8
not provided	Uncertain significance (2)	criteria provided, multiple submitters, no conflicts	Jan 12, 2023	RCV003477510.1
FANCA-related disorder	Uncertain significance (1)	no assertion criteria provided	Jul 17, 2024	RCV004742266.1

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 (Apr 18, 2017)	criteria provided, single submitter (Counsyl Autosomal Recessive and X-Linked Classification Criteria (2018)) Method: clinical testing	Fanconi anemia complementation group A Affected status: unknown Allele origin: unknown	Counsyl Accession: SCV000790989.1 First in ClinVar: Aug 05, 2018 Last updated: Aug 05, 2018
Uncertain significance (Nov 26, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Fanconi anemia complementation group A Affected status: yes Allele origin: unknown	Baylor Genetics Accession: SCV001522900.1 First in ClinVar: Mar 22, 2021 Last updated: Mar 22, 2021	Comment: This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Uncertain significance (Jan 26, 2022)	criteria provided, single submitter (Sema4 Curation Guidelines) Method: curation	Fanconi anemia Affected status: unknown Allele origin: germline	Sema4, Sema4 Accession: SCV002535037.1 First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022 Comment: To the best of our knowledge, the FANCA c.4015C>T (p.L1339F) variant has not been reported in individuals with FANCA-related disease. It was observed in 7/24954 … (more) To the best of our knowledge, the FANCA c.4015C>T (p.L1339F) variant has not been reported in individuals with FANCA-related disease. It was observed in 7/24954 chromosomes of the African/African American subpopulation in the large and broad cohorts of the Genome Aggregation Database (http://gnomad.broadinstitute.org, PMID: 32461654). The variant has been reported in ClinVar (Variation ID 134280). Functional studies have not been performed, and in silico predictions of the variant's effect on protein function are inconclusive. 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)
Uncertain significance (Jan 12, 2023)	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: SCV004218598.1 First in ClinVar: Jan 06, 2024 Last updated: Jan 06, 2024	Publications: PubMed (2) PubMed: 24728327‚ 31698007 Comment: The frequency of this variant in the general population, 0.00028 (7/24954 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the … (more) The frequency of this variant in the general population, 0.00028 (7/24954 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported only in a healthy individual (PMID: 24728327 (2014)) and as a somatic variant in an individual with prostate cancer (PMID: 31698007 (2019)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is benign or damaging. Based on the available information, we are unable to determine the clinical significance of this variant. (less)
Uncertain significance (May 31, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Fanconi anemia complementation group A Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV003832355.2 First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024
Uncertain significance (Sep 13, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Not provided Affected status: unknown Allele origin: germline	Mayo Clinic Laboratories, Mayo Clinic Accession: SCV004224278.1 First in ClinVar: Jan 06, 2024 Last updated: Jan 06, 2024	Number of individuals with the variant: 1
Likely benign (Jan 29, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Fanconi anemia Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000965472.4 First in ClinVar: Aug 14, 2019 Last updated: Feb 20, 2024
Uncertain significance (Sep 16, 2020)	no assertion criteria provided Method: clinical testing	Fanconi anemia, group A Affected status: unknown Allele origin: germline	Natera, Inc. Accession: SCV001458744.1 First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021
Uncertain significance (Jul 17, 2024)	no assertion criteria provided Method: clinical testing	FANCA-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV005341441.1 First in ClinVar: Oct 08, 2024 Last updated: Oct 08, 2024	Comment: The FANCA c.4015C>T variant is predicted to result in the amino acid substitution p.Leu1339Phe. This variant was reported in a study of germline variation in … (more) The FANCA c.4015C>T variant is predicted to result in the amino acid substitution p.Leu1339Phe. This variant was reported in a study of germline variation in a healthy, ancestrally diverse cohort (Table S1, Bodian et al. 2014. PubMed ID: 24728327). This variant is reported in 0.028% of alleles in individuals of African descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. (less)
not provided (Sep 19, 2013)	no classification provided Method: reference population	AllHighlyPenetrant Affected status: unknown Allele origin: germline	ITMI Accession: SCV000085121.1 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

Comment:

The frequency of this variant in the general population, 0.00028 (7/24954 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported only in a healthy individual (PMID: 24728327 (2014)) and as a somatic variant in an individual with prostate cancer (PMID: 31698007 (2019)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is benign or damaging. Based on the available information, we are unable to determine the clinical significance of this variant.

Comment:

The FANCA c.4015C>T variant is predicted to result in the amino acid substitution p.Leu1339Phe. This variant was reported in a study of germline variation in a healthy, ancestrally diverse cohort (Table S1, Bodian et al. 2014. PubMed ID: 24728327). This variant is reported in 0.028% of alleles in individuals of African descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

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:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Plasmacytoid acinar adenocarcinoma of the prostate: a newly described variant of prostate cancer.	Al-Hussain T	Human pathology	2019	PMID: 31698007
Germline variation in cancer-susceptibility genes in a healthy, ancestrally diverse cohort: implications for individual genome sequencing.	Bodian DL	PloS one	2014	PMID: 24728327

Text-mined citations for rs149775657 ...

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 Oct 13, 2024

ClinVar Genomic variation as it relates to human health

NM_000135.4(FANCA):c.4015C>T (p.Leu1339Phe)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs149775657 ...