VCV000134256.43 - ClinVar

NM_000135.4(FANCA):c.2574C>G (p.Ser858Arg)

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.

(19)

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.

Benign/Likely benign

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.2574C>G (p.Ser858Arg)

Variation ID: 134256 Accession: VCV000134256.43

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 16q24.3 16: 89767168 (GRCh38) [ NCBI UCSC ] 16: 89833576 (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 20, 2024	Aug 1, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000135.4:c.2574C>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000126.2:p.Ser858Arg	missense
NM_000135.3:c.2574C>G
NM_001286167.3:c.2574C>G	NP_001273096.1:p.Ser858Arg	missense
NC_000016.10:g.89767168G>C
NC_000016.9:g.89833576G>C
NG_011706.1:g.54490C>G
LRG_495:g.54490C>G
LRG_495t1:c.2574C>G
	O15360:p.Ser858Arg

... more HGVS ... less HGVS

Protein change

S858R

Other names

Canonical SPDI

NC_000016.10:89767167:G:C

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.

0.00938 (C)

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

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00531

Trans-Omics for Precision Medicine (TOPMed) 0.00565

The Genome Aggregation Database (gnomAD) 0.00567

1000 Genomes Project 30x 0.00906

1000 Genomes Project 0.00938

The Genome Aggregation Database (gnomAD), exomes 0.01005

Exome Aggregation Consortium (ExAC) 0.01031

Links

ClinGen: CA212608 UniProtKB: O15360#VAR_017498 dbSNP: rs17233141 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

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	Benign (5)	criteria provided, multiple submitters, no conflicts	Feb 18, 2022	RCV000120929.13
Fanconi anemia complementation group A	Likely benign (5)	criteria provided, multiple submitters, no conflicts	May 18, 2021	RCV000202580.11
Fanconi anemia	Benign (2)	criteria provided, multiple submitters, no conflicts	Jan 31, 2024	RCV000206151.16
not provided	Benign/Likely benign (6)	criteria provided, multiple submitters, no conflicts	Aug 1, 2024	RCV000514362.20
FANCA-related disorder	Likely benign (1)	no assertion criteria provided	Jul 16, 2019	RCV003915204.2

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.
Benign (Feb 18, 2022)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV002103357.1 First in ClinVar: Mar 12, 2022 Last updated: Mar 12, 2022	Comment: Variant summary: FANCA c.2574C>G (p.Ser858Arg) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign … (more) Variant summary: FANCA c.2574C>G (p.Ser858Arg) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.01 in 251444 control chromosomes, predominantly at a frequency of 0.032 within the South Asian subpopulation in the gnomAD database, including 26 homozygotes. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 15 fold of the estimated maximal expected allele frequency for a pathogenic variant in FANCA causing Fanconi Anemia phenotype (0.0022), strongly suggesting that the variant is a benign polymorphism found primarily in populations of South Asian origin. To our knowledge, no experimental evidence demonstrating its impact on protein function have been reported. Ten ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (n=1), likely benign (n=3), benign (n=4) and pathogenic (n=2). Based on the evidence outlined above, the variant was classified as benign. (less)
Benign (Jun 08, 2021)	criteria provided, single submitter (Quest Diagnostics criteria) Method: clinical testing	not specified Affected status: unknown Allele origin: unknown	Quest Diagnostics Nichols Institute San Juan Capistrano Accession: SCV002047241.2 First in ClinVar: Jan 03, 2022 Last updated: Dec 31, 2022	Publications: PubMed (8) PubMed: 12955722‚ 10094191‚ 11091222‚ 24728327‚ 27148581‚ 15591268‚ 21279724‚ 26799702
Likely benign (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: not provided	not provided (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Breakthrough Genomics, Breakthrough Genomics Accession: SCV005219761.1 First in ClinVar: Sep 29, 2024 Last updated: Sep 29, 2024
Benign (Aug 01, 2024)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV004143605.10 First in ClinVar: Nov 20, 2023 Last updated: Oct 20, 2024	Comment: FANCA: BP4, BS1, BS2 Number of individuals with the variant: 68
Likely benign (Mar 20, 2017)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: not provided Allele origin: germline	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics Accession: SCV000610421.1 First in ClinVar: Nov 05, 2017 Last updated: Nov 05, 2017
Likely benign (Apr 27, 2017)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Fanconi anemia complementation group A Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000399841.3 First in ClinVar: Dec 06, 2016 Last updated: May 31, 2020	Comment: This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more) This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. (less)
Benign (Sep 01, 2017)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not specified Affected status: no Allele origin: germline	Genetic Services Laboratory, University of Chicago Accession: SCV000594634.2 First in ClinVar: Mar 08, 2017 Last updated: Jun 13, 2020
Likely benign (May 18, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Fanconi anemia complementation group A Affected status: no Allele origin: germline	Genome-Nilou Lab Accession: SCV001737170.1 First in ClinVar: Jun 19, 2021 Last updated: Jun 19, 2021	Sex: mixed
Benign (May 16, 2019)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000512960.4 First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017	Comment: This variant is associated with the following publications: (PMID: 24728327, 11091222, 30249500, 21279724, 24082139, 10094191, 27884173, 27153395, 26740942, 15591268, 23021409, 27148581, 30553997, 26799702, 26119737, 29084058, … (more) This variant is associated with the following publications: (PMID: 24728327, 11091222, 30249500, 21279724, 24082139, 10094191, 27884173, 27153395, 26740942, 15591268, 23021409, 27148581, 30553997, 26799702, 26119737, 29084058, 25231023, 12955722) (less)
Benign (Jul 21, 2020)	criteria provided, single submitter (Sema4 Curation Guidelines) Method: curation	Fanconi anemia Affected status: unknown Allele origin: germline	Sema4, Sema4 Accession: SCV002534957.1 First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022
Benign (Jan 31, 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: SCV000262266.11 First in ClinVar: Jan 31, 2016 Last updated: Feb 14, 2024
Likely benign (-)	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: SCV001807935.1 First in ClinVar: Aug 25, 2021 Last updated: Aug 25, 2021
Benign (-)	no assertion criteria provided Method: clinical testing	not specified Affected status: yes Allele origin: germline	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) Study: VKGL Data-share Consensus Accession: SCV001800807.1 First in ClinVar: Aug 21, 2021 Last updated: Aug 21, 2021
Likely benign (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Genome Diagnostics Laboratory, University Medical Center Utrecht Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001927739.1 First in ClinVar: Sep 26, 2021 Last updated: Sep 26, 2021
Likely benign (Jul 16, 2019)	no assertion criteria provided Method: clinical testing	FANCA-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV004733489.2 First in ClinVar: Mar 16, 2024 Last updated: Oct 08, 2024	Comment: This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
not provided (Sep 19, 2013)	no classification provided Method: reference population	AllHighlyPenetrant Affected status: unknown Allele origin: germline	ITMI Accession: SCV000085097.1 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
Pathogenic (Oct 22, 2015)	Flagged submission flagged submission Method: research Reason: Outlier claim with insufficient supporting evidence Source: ClinGen	Fanconi anemia complementation group A (Autosomal recessive inheritance) Affected status: no Allele origin: germline	McDonnell Genome Institute, Washington University in St. Louis Accession: SCV000257331.1 First in ClinVar: Dec 21, 2015 Last updated: Dec 21, 2015	Number of individuals with the variant: 1 Age: 30-39 years Sex: male Ethnicity/Population group: Caucasians Tissue: Skin
Pathogenic (Feb 28, 2020)	Flagged submission flagged submission Method: curation Reason: Outlier claim with insufficient supporting evidence Source: ClinGen	Fanconi anemia complementation group A Affected status: yes Allele origin: germline	Leiden Open Variation Database Accession: SCV001425828.1 First in ClinVar: Sep 27, 2020 Last updated: Sep 27, 2020	Publications: PubMed (3) PubMed: 10094191‚ 11091222‚ 12955722 Comment: Curator: Arleen D. Auerbach. Submitter to LOVD: Arleen D. Auerbach.
Uncertain significance (Jan 09, 2020)	Flagged submission flagged submission Method: clinical testing Reason: Outlier claim with insufficient supporting evidence Source: ClinGen	Fanconi anemia, group A Affected status: unknown Allele origin: germline	Natera, Inc. Accession: SCV001458827.1 First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021
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Comment:

Variant summary: FANCA c.2574C>G (p.Ser858Arg) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.01 in 251444 control chromosomes, predominantly at a frequency of 0.032 within the South Asian subpopulation in the gnomAD database, including 26 homozygotes. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 15 fold of the estimated maximal expected allele frequency for a pathogenic variant in FANCA causing Fanconi Anemia phenotype (0.0022), strongly suggesting that the variant is a benign polymorphism found primarily in populations of South Asian origin. To our knowledge, no experimental evidence demonstrating its impact on protein function have been reported. Ten ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (n=1), likely benign (n=3), benign (n=4) and pathogenic (n=2). Based on the evidence outlined above, the variant was classified as benign.

Comment:

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.

Comment:

This variant is associated with the following publications: (PMID: 24728327, 11091222, 30249500, 21279724, 24082139, 10094191, 27884173, 27153395, 26740942, 15591268, 23021409, 27148581, 30553997, 26799702, 26119737, 29084058, 25231023, 12955722)

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 common founding clone with TP53 and PTEN mutations gives rise to a concurrent germ cell tumor and acute megakaryoblastic leukemia.	Lu C	Cold Spring Harbor molecular case studies	2016	PMID: 27148581
FANCA Gene Mutations with 8 Novel Molecular Changes in Indian Fanconi Anemia Patients.	Solanki A	PloS one	2016	PMID: 26799702
Germline variation in cancer-susceptibility genes in a healthy, ancestrally diverse cohort: implications for individual genome sequencing.	Bodian DL	PloS one	2014	PMID: 24728327
Mutations in Fanconi anemia genes and the risk of esophageal cancer.	Akbari MR	Human genetics	2011	PMID: 21279724
Genetics of the FANCA gene in familial pancreatic cancer.	Rogers CD	Journal of medical genetics	2004	PMID: 15591268
Spectrum of FANCA mutations in Italian Fanconi anemia patients: identification of six novel alleles and phenotypic characterization of the S858R variant.	Savino M	Human mutation	2003	PMID: 12955722
Fanconi anaemia group A (FANCA) mutations in Israeli non-Ashkenazi Jewish patients.	Tamary H	British journal of haematology	2000	PMID: 11091222
Heterogeneous spectrum of mutations in the Fanconi anaemia group A gene.	Wijker M	European journal of human genetics : EJHG	1999	PMID: 10094191

Text-mined citations for rs17233141 ...

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 20, 2024

ClinVar Genomic variation as it relates to human health

NM_000135.4(FANCA):c.2574C>G (p.Ser858Arg)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs17233141 ...