Submissions for variant NM_000136.3(FANCC):c.456+4A>T (rs104886456)

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000562912	SCV000673287	pathogenic	Hereditary cancer-predisposing syndrome	2017-10-31	criteria provided, single submitter	clinical testing	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 in trans with a mutation or mutation is homozygous,In silico models in agreement (deleterious) and/or completely conserved position in appropriate species
Center for Pediatric Genomic Medicine,Children's Mercy Hospital and Clinics	RCV000115354	SCV000281326	pathogenic	not provided	2015-02-11	criteria provided, single submitter	clinical testing
Counsyl	RCV000012825	SCV000677963	pathogenic	Fanconi anemia, complementation group C	2015-06-14	criteria provided, single submitter	clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics	RCV000115354	SCV000230847	pathogenic	not provided	2015-04-07	criteria provided, single submitter	clinical testing
Fulgent Genetics,Fulgent Genetics	RCV000012825	SCV000894484	pathogenic	Fanconi anemia, complementation group C	2018-10-31	criteria provided, single submitter	clinical testing
GeneDx	RCV000115354	SCV000149263	pathogenic	not provided	2018-07-17	criteria provided, single submitter	clinical testing	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 FANCC gene. This variant has been shown to result in the skipping of exon 5 due to abnormal gene splicing (Whitney 1993). FANCC c.456+4A>T, historically referred to as IVS4+4A>T, has been published in both the compound heterozygous and homozygous state in individuals with Fanconi Anemia (Whitney 1993), and is recognized as a pathogenic founder variant in the Ashkenazi Jewish population with a carrier frequency of approximately 1.1% (Verlander 1995, Futaki 2000, Chandrasekharappa 2013). Additionally, this variant has been observed in at least one woman with a history of early-onset breast cancer (Laitman 2015). Based on current evidence, we consider FANCC c.456+4A>T to be pathogenic.
GeneReviews	RCV000012825	SCV000057808	pathogenic	Fanconi anemia, complementation group C	2016-09-22	no assertion criteria provided	literature only
Illumina Clinical Services Laboratory,Illumina	RCV000012825	SCV000916270	pathogenic	Fanconi anemia, complementation group C	2018-10-05	criteria provided, single submitter	clinical testing	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 of available literature, the c.456+4A>T variant has been identified in a homozygous state in 12 probands, in a heterozygous state in one proband in whom a second variant was not identified, and in a heterozygous state in seven unaffected family members (Whitney et al. 1993; Futaki et al. 2000; Auerbach, 2009). The c.456+4A>T variant was absent from 25 controls and is reported at a frequency of 0.006016 in the European (non-Finnish) population of the Genome Aggregation Database. Verlander et al. (1995) determined that the carrier frequency of the c.456+4A>T variant in the Ashkenazi Jewish population is approximately one in 89, or 1.1%. RT-PCR analysis indicated the c.456+4A>T variant disrupts splicing and results in the production of two abnormal products, an 111bp in-frame deletion and a 40bp partial removal of exon 4 (Whitney et al. 1993). Patient-derived fibroblasts demonstrated that the c.456+4A>T variant significantly reduced DNA end-joining activity compared with wild type cells (Donahue et al. 2004). Based on the evidence, the c.456+4A>T variant is classified as pathogenic for Fanconi anemia. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Integrated Genetics/Laboratory Corporation of America	RCV000012825	SCV000695432	pathogenic	Fanconi anemia, complementation group C	2016-01-18	criteria provided, single submitter	clinical testing	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 splice donor site for the variant, which is predicted to increase exon skipping. These in silico predictions are supported by functional studies showing that this variant leads to a truncated protein product. This variant is found in 28/117194 control chromosomes at a frequency of 0.0002389, which does not significantly exceed maximal expected frequency of a pathogenic FANCC allele (0.0017678).The variant has been cited in multiple severe FA patients in homozygous state and in mild FA patients in compound heterozygous state. In addition, multiple clinical diagnostic labs classified this variant as pathogenic. This intronic variant is considered a known common disease variant in the literature, therefore, this is a disease variant and was classified as pathogenic.
Invitae	RCV000197192	SCV000253765	pathogenic	Fanconi anemia	2018-12-28	criteria provided, single submitter	clinical testing	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, but it affects a nucleotide within the consensus splice site of the intron. This variant is present in population databases (rs104886456, ExAC 0.04%). This variant has been well described in the literature as causative for Fanconi anemia in multiple populations (PMID: 8348157, 8081385, 10666230). In the literature, this variant is also known as IVS+4A>T. ClinVar has an entry for this variant (Variation ID: 12045). Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Experimental studies have shown that this variant disrupts splicing (PMID: 8348157). For these reasons, this variant has been classified as Pathogenic.
Mendelics	RCV000012825	SCV000838356	pathogenic	Fanconi anemia, complementation group C	2018-07-02	criteria provided, single submitter	clinical testing
OMIM	RCV000012825	SCV000033065	pathogenic	Fanconi anemia, complementation group C	2001-06-27	no assertion criteria provided	literature only