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NM_000136.3(FANCC):c.456+4A>T

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Interpretation:
Pathogenic​

Review status:
criteria provided, multiple submitters, no conflicts
Submissions:
12 (Most recent: Mar 28, 2019)
Last evaluated:
Dec 28, 2018
Accession:
VCV000012045.4
Variation ID:
12045
Description:
single nucleotide variant
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NM_000136.3(FANCC):c.456+4A>T

Allele ID
27084
Variant type
single nucleotide variant
Variant length
1 bp
Cytogenetic location
9q22.32
Genomic location
9: 95172033 (GRCh38) GRCh38 UCSC
9: 97934315 (GRCh37) GRCh37 UCSC
HGVS
Nucleotide Protein Molecular
consequence
NC_000009.12:g.95172033T>A
NC_000009.11:g.97934315T>A
LRG_497t1:c.456+4A>T
... more HGVS
Protein change
-
Other names
IVS5+4A>T
IVS4+4A>T
IVS4, A-T, +4
Functional consequence
-
Global minor allele frequency (GMAF)
-

Allele frequency
The Genome Aggregation Database (gnomAD) 0.00013
The Genome Aggregation Database (gnomAD), exomes 0.00029
Exome Aggregation Consortium (ExAC) 0.00024
Trans-Omics for Precision Medicine (TOPMed) 0.00022
Links
ClinGen: CA287219
OMIM: 613899.0003
dbSNP: rs104886456
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Aggregate interpretations per condition

Interpreted condition Interpretation Number of submissions Review status Last evaluated Variation/condition record
Pathogenic 7 criteria provided, multiple submitters, no conflicts Oct 31, 2018 RCV000012825.10
Pathogenic 3 criteria provided, multiple submitters, no conflicts Jul 17, 2018 RCV000115354.6
Pathogenic 1 criteria provided, single submitter Dec 28, 2018 RCV000197192.8
Pathogenic 1 criteria provided, single submitter Oct 31, 2017 RCV000562912.1
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Gene OMIM ClinGen Gene Dosage Sensitivity Curation Variation viewer Related variants
HI score Help TS score Help Within gene All
FANCC - - GRCh38
GRCh37
243 642

Submitted interpretations and evidence

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Interpretation
(Last evaluated)
Review status
(Assertion criteria)
Condition
(Inheritance)
Submitter Supporting information
Pathogenic
(Jan 18, 2016)
criteria provided, single submitter
Method: clinical testing
Fanconi anemia, complementation group C
Allele origin: germline
Integrated Genetics/Laboratory Corporation of America
Accession: SCV000695432.1
Submitted: (Jan 25, 2018)
Evidence details
Publications
PubMed (1)
Comment:
Variant summary: FANCC c.456+4A>T affects a conserved intronic nucleotide. Mutation Taster predicts a damaging outcome for this variant, and 4/5 Alamut algorithms predict a weaker ... (more)
Pathogenic
(Oct 31, 2017)
criteria provided, single submitter
Method: clinical testing
Hereditary cancer-predisposing syndrome
Allele origin: germline
Ambry Genetics
Accession: SCV000673287.2
Submitted: (Jul 30, 2018)
Evidence details
Publications
PubMed (10)
Comment:
Lines of evidence used in support of classification: Deficient protein function by in vitro/ex vivo assay,Detected in individual(s) satisfying established diagnostic criteria for classic disease ... (more)
Pathogenic
(Oct 31, 2018)
criteria provided, single submitter
Method: clinical testing
Fanconi anemia, complementation group C
Allele origin: unknown
Fulgent Genetics,Fulgent Genetics
Accession: SCV000894484.1
Submitted: (Nov 14, 2018)
Evidence details
Publications
PubMed (1)
DOI: 10.1038/gim.2015.30
Pathogenic
(Jul 17, 2018)
criteria provided, single submitter
Method: clinical testing
Not Provided
Allele origin: germline
GeneDx
Accession: SCV000149263.14
Submitted: (Jan 29, 2019)
Evidence details
Comment:
This pathogenic variant is denoted FANCC c.456+4A>T or IVS5+4A>T and consists of an A>T nucleotide substitution at the +4 position of exon 5 of the ... (more)
Pathogenic
(Feb 11, 2015)
criteria provided, single submitter
Method: clinical testing
not provided
Allele origin: germline
Center for Pediatric Genomic Medicine,Children's Mercy Hospital and Clinics
Accession: SCV000281326.2
Submitted: (Oct 05, 2017)
Evidence details
Pathogenic
(Jun 14, 2015)
criteria provided, single submitter
Method: clinical testing
Fanconi anemia, complementation group C
Allele origin: unknown
Counsyl
Accession: SCV000677963.1
Submitted: (Jun 22, 2017)
Evidence details
Publications
PubMed (6)
Pathogenic
(Jul 02, 2018)
criteria provided, single submitter
Method: clinical testing
Fanconi anemia, complementation group C
Allele origin: unknown
Mendelics
Accession: SCV000838356.1
Submitted: (Aug 20, 2018)
Evidence details
Pathogenic
(Apr 07, 2015)
criteria provided, single submitter
Method: clinical testing
not provided
Allele origin: germline
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics
Accession: SCV000230847.5
Submitted: (Sep 19, 2018)
Evidence details
Other databases
http://www.egl-eurofins.com/em...
http://www.ncbi.nlm.nih.gov/si...
Pathogenic
(Oct 05, 2018)
criteria provided, single submitter
Method: clinical testing
Fanconi anemia, complementation group C
Allele origin: germline
Illumina Clinical Services Laboratory,Illumina
Accession: SCV000916270.1
Submitted: (Feb 01, 2019)
Evidence details
Publications
PubMed (5)
Comment:
The FANCC c.456+4A>T variant is a common pathogenic FANCC variant, particularly in the Ashkenazi Jewish population (Verlander et al. 1995; Auerbach, 2009). Across a selection ... (more)
Pathogenic
(Dec 28, 2018)
criteria provided, single submitter
Method: clinical testing
Fanconi anemia
Allele origin: germline
Invitae
Accession: SCV000253765.8
Submitted: (Mar 28, 2019)
Evidence details
Publications
PubMed (4)
Comment:
This sequence change falls in intron 5 of the FANCC gene. It does not directly change the encoded amino acid sequence of the FANCC protein, ... (more)
Pathogenic
(Jun 27, 2001)
no assertion criteria provided
Method: literature only
FANCONI ANEMIA, COMPLEMENTATION GROUP C
Allele origin: germline
OMIM
Accession: SCV000033065.2
Submitted: (Dec 30, 2010)
Evidence details
Publications
PubMed (4)
Pathogenic
(Sep 22, 2016)
no assertion criteria provided
Method: literature only
Fanconi anemia, complementation group C
Allele origin: germline
GeneReviews
Accession: SCV000057808.2
Submitted: (Sep 27, 2016)
Evidence details
Publications
PubMed (3)
Other databases
http://www.ncbi.nlm.nih.gov/bo...

Citations for this variant

Title Author Journal Year Link
Fanconi Anemia Mehta PA - 2018 PMID: 20301575
Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria. Nykamp K Genetics in medicine : official journal of the American College of Medical Genetics 2017 PMID: 28492532
The risk for developing cancer in Israeli ATM, BLM, and FANCC heterozygous mutation carriers. Laitman Y Cancer genetics 2016 PMID: 26778106
Pathogenic and likely pathogenic variant prevalence among the first 10,000 patients referred for next-generation cancer panel testing. Susswein LR Genetics in medicine : official journal of the American College of Medical Genetics 2016 PMID: 26681312
Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Richards S Genetics in medicine : official journal of the American College of Medical Genetics 2015 PMID: 25741868
RNA splicing. The human splicing code reveals new insights into the genetic determinants of disease. Xiong HY Science (New York, N.Y.) 2015 PMID: 25525159
Massively parallel sequencing, aCGH, and RNA-Seq technologies provide a comprehensive molecular diagnosis of Fanconi anemia. Chandrasekharappa SC Blood 2013 PMID: 23613520
A Dutch Fanconi Anemia FANCC Founder Mutation in Canadian Manitoba Mennonites. de Vries Y Anemia 2012 PMID: 22701786
Fanconi anemia and its diagnosis. Auerbach AD Mutation research 2009 PMID: 19622403
Should chromosome breakage studies be performed in patients with VACTERL association? Faivre L American journal of medical genetics. Part A 2005 PMID: 16015582
Fanconi anemia in Ashkenazi Jews. Kutler DI Familial cancer 2004 PMID: 15516848
Intermediate DNA repair activity associated with the 322delG allele of the fanconi anemia complementation group C gene. Donahue SL Journal of molecular biology 2004 PMID: 15364573
Preimplantation diagnosis for Fanconi anemia combined with HLA matching. Verlinsky Y JAMA 2001 PMID: 11427142
The IVS4 + 4 A to T mutation of the fanconi anemia gene FANCC is not associated with a severe phenotype in Japanese patients. Futaki M Blood 2000 PMID: 10666230
Phenotypic consequences of mutations in the Fanconi anemia FAC gene: an International Fanconi Anemia Registry study. Gillio AP Blood 1997 PMID: 9207444
Clinical variability of Fanconi anemia (type C) results from expression of an amino terminal truncated Fanconi anemia complementation group C polypeptide with partial activity. Yamashita T Blood 1996 PMID: 8639804
Carrier frequency of the IVS4 + 4 A-->T mutation of the Fanconi anemia gene FAC in the Ashkenazi Jewish population. Verlander PC Blood 1995 PMID: 7492758
Mutation analysis of the Fanconi anemia gene FACC. Verlander PC American journal of human genetics 1994 PMID: 8128956
The Ashkenazi Jewish Fanconi anemia mutation: incidence among patients and carrier frequency in the at-risk population. Whitney MA Human mutation 1994 PMID: 8081385
A common mutation in the FACC gene causes Fanconi anaemia in Ashkenazi Jews. Whitney MA Nature genetics 1993 PMID: 8348157
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=FANCC - - - -
http://www.ncbi.nlm.nih.gov/books/NBK1401/ - - - -
http://www.ncbi.nlm.nih.gov/sites/GeneTests/review/gene/FANCC - - - -

Record last updated Nov 09, 2019