VCV000974247.10 - ClinVar

NM_000135.4(FANCA):c.2604_2609del

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.

(4)

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.

Pathogenic/Likely pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000135.4(FANCA):c.2604_2609del

Variation ID: 974247 Accession: VCV000974247.10

Type and length

Microsatellite, 6 bp

Location

Cytogenetic: 16q24.3 16: 89765059-89765064 (GRCh38) [ NCBI UCSC ] 16: 89831467-89831472 (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	Sep 27, 2020	Feb 20, 2024	Sep 21, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_000135.4:c.2604_2609del MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NM_000135.4:c.2604_2609delTCAGTT MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.		splice acceptor
NC_000016.10:g.89765062TGAAAC[1]
NC_000016.9:g.89831470TGAAAC[1]
NG_011706.1:g.56588TCAGTT[1]
NG_011706.1:g.56594_56599del
LRG_495:g.56588TCAGTT[1]
LRG_495t1:c.2604_2609del

... more HGVS ... less HGVS

Protein change

Other names

Canonical SPDI

NC_000016.10:89765058:AACTGAAACTGAAAC:AACTGAAAC

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.

Links

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	4167	5325
LOC130059837	-	-	-	GRCh38	-	137

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.
Fanconi anemia complementation group A	Likely pathogenic (3)	criteria provided, multiple submitters, no conflicts	Nov 29, 2022	RCV001256500.11
Fanconi anemia	Pathogenic (1)	criteria provided, single submitter	Sep 21, 2023	RCV001879793.14

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.
Likely pathogenic (Dec 15, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Fanconi anemia complementation group A Affected status: no Allele origin: germline	Department of Pediatrics, Memorial Sloan Kettering Cancer Center Accession: SCV001478119.1 First in ClinVar: Jun 19, 2021 Last updated: Jun 19, 2021	Publications: PubMed (1) PubMed: 28873162
Likely pathogenic (Nov 29, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Fanconi anemia complementation group A Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV004196603.1 First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023
Pathogenic (Sep 21, 2023)	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: SCV002218142.3 First in ClinVar: Mar 28, 2022 Last updated: Feb 20, 2024	Publications: PubMed (3) PubMed: 15643609‚ 17924555‚ 29098742 Comment: This variant, c.2604_2609del, results in the deletion of 2 amino acid(s) of the FANCA protein (p.Gln869_Phe870del), but otherwise preserves the integrity of the reading frame. … (more) This variant, c.2604_2609del, results in the deletion of 2 amino acid(s) of the FANCA protein (p.Gln869_Phe870del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs745864224, gnomAD 0.0009%). This variant has been observed in individual(s) with clinical features of Fanconi anemia (PMID: 15643609, 17924555). ClinVar contains an entry for this variant (Variation ID: 974247). This variant disrupts a region of the FANCA protein in which other variant(s) (p.Gln869Pro) have been determined to be pathogenic (PMID: 15643609, 17924555, 29098742; Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (Feb 28, 2020)	no assertion criteria provided Method: curation	Fanconi anemia complementation group A Affected status: yes Allele origin: germline	Leiden Open Variation Database Accession: SCV001425965.1 First in ClinVar: Sep 27, 2020 Last updated: Sep 27, 2020	Publications: PubMed (1) PubMed: 17924555 Comment: Curator: Arleen D. Auerbach. Submitters to LOVD: Arleen D. Auerbach, Daniela Pilonetto, Johan de Winter.

Comment:

This variant, c.2604_2609del, results in the deletion of 2 amino acid(s) of the FANCA protein (p.Gln869_Phe870del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs745864224, gnomAD 0.0009%). This variant has been observed in individual(s) with clinical features of Fanconi anemia (PMID: 15643609, 17924555). ClinVar contains an entry for this variant (Variation ID: 974247). This variant disrupts a region of the FANCA protein in which other variant(s) (p.Gln869Pro) have been determined to be pathogenic (PMID: 15643609, 17924555, 29098742; Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.

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
A comprehensive approach to identification of pathogenic FANCA variants in Fanconi anemia patients and their families.	Kimble DC	Human mutation	2018	PMID: 29098742
Mutation Detection in Patients With Advanced Cancer by Universal Sequencing of Cancer-Related Genes in Tumor and Normal DNA vs Guideline-Based Germline Testing.	Mandelker D	JAMA	2017	PMID: 28873162
Genetic subtyping of Fanconi anemia by comprehensive mutation screening.	Ameziane N	Human mutation	2008	PMID: 17924555
Spectrum of sequence variations in the FANCA gene: an International Fanconi Anemia Registry (IFAR) study.	Levran O	Human mutation	2005	PMID: 15643609

Text-mined citations for this variant ...

Record last updated Nov 25, 2024

ClinVar Genomic variation as it relates to human health

NM_000135.4(FANCA):c.2604_2609del

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...