Total submissions: 16
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Gene |
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. |
EGL Genetic Diagnostics, |
RCV000115354 | SCV000230847 | pathogenic | not provided | 2015-04-07 | criteria provided, single submitter | clinical testing | |
Invitae | RCV000197192 | SCV000253765 | pathogenic | Fanconi anemia | 2020-01-07 | 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. |
Center for Pediatric Genomic Medicine, |
RCV000115354 | SCV000281326 | pathogenic | not provided | 2015-02-11 | criteria provided, single submitter | clinical testing | |
Ambry Genetics | RCV000562912 | SCV000673287 | pathogenic | Hereditary cancer-predisposing syndrome | 2018-11-13 | criteria provided, single submitter | clinical testing | The c.456+4A>T intronic pathogenic mutation results from an A to T substitution 4 nucleotides after coding exon 4 in the FANCC gene. This well-described mutation has been reported in multiple homozygous and compound heterozygous individuals with Fanconi anemia, and it is the most common mutation in FANCC in individuals of Ashkenazi Jewish descent (Whitney MA et al. Nat. Genet. 1993 Jun;4:202-5; Whitney MA et al. Hum. Mutat., 1994;3:339-41; Verlander PC et al. Am. J. Hum. Genet. 1994 Apr;54:595-601; Yamashita T et al. Blood. 1996 May;87:4424-32; Futaki M et al. Blood. 2000 Feb;95:1493-8; Kutler DI et al. Fam. Cancer. 2004;3:241-8; Chandrasekharappa SC et al. Blood. 2013 May;121:e138-4; Aftab I et al. Turk J Med Sci, 2017 Apr;47:391-398). This alteration was also identified in 7/10030 consecutive patients referred for evaluation by an NGS hereditary cancer panel (Susswein LR et al. Genet. Med. 2016 Aug;18:823-32). This nucleotide position is highly conserved in available vertebrate species. Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to weaken the efficiency of the native splice donor site; furthermore, RT-PCR studies have shown that this alteration results in a truncated protein product compared to the wild-type allele (Whitney MA et al. Nat. Genet. 1993 Jun;4:202-5). Of note, this mutation is also designated as IVS4+4A>T and c.711+4A>T in published literature. Based on the available evidence, this alteration is classified as a pathogenic mutation. |
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. |
Mendelics | RCV000012825 | SCV000838356 | pathogenic | Fanconi anemia, complementation group C | 2018-07-02 | criteria provided, single submitter | clinical testing | |
Fulgent Genetics, |
RCV000012825 | SCV000894484 | pathogenic | Fanconi anemia, complementation group C | 2018-10-31 | criteria provided, single submitter | clinical testing | |
Illumina Clinical Services Laboratory, |
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. |
Baylor Genetics | RCV000012825 | SCV001163628 | pathogenic | Fanconi anemia, complementation group C | criteria provided, single submitter | clinical testing | ||
Myriad Women's Health, |
RCV000012825 | SCV001194186 | pathogenic | Fanconi anemia, complementation group C | 2019-11-12 | criteria provided, single submitter | clinical testing | NM_000136.2(FANCC):c.456+4A>T is classified as pathogenic in the context of Fanconi anemia. Sources cited for classification include the following: 8081385, 7492758, 8348157, 11427142, 9207444, and 10666230. Classification of NM_000136.2(FANCC):c.456+4A>T is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. |
Institute of Human Genetics, |
RCV000012825 | SCV001439971 | pathogenic | Fanconi anemia, complementation group C | 2019-01-01 | criteria provided, single submitter | clinical testing | |
OMIM | RCV000012825 | SCV000033065 | pathogenic | Fanconi anemia, complementation group C | 2001-06-27 | no assertion criteria provided | literature only | |
Gene |
RCV000012825 | SCV000057808 | pathogenic | Fanconi anemia, complementation group C | 2016-09-22 | no assertion criteria provided | literature only | |
Reproductive Health Research and Development, |
RCV000197192 | SCV001142398 | pathogenic | Fanconi anemia | 2020-01-06 | no assertion criteria provided | curation | NG_011707.1(NM_000136.2):c.456+4A>T is also known as IVS4+4A>T in literatures. It has an allele frequency of 0.006 in Ashkenazi Jewish subpopulation in the gnomAD database. Whitney et al reported that this variant resulted exon skipping due to abnormal gene splicing (PMID: 8348157). FANCC c.456+4A>T has been published in both the compound heterozygous and homozygous state in individuals with Fanconi Anemia (PMID: 8348157). It is also determined as a pathogenic founder variant in the Ashkenazi Jewish population(PMID: 7492758). Taken together, we interprete this variant as Pathogenic/Likely pathogenic. ACMG/AMP Criteria applied: PS3; PM3_Strong; PP4. |
Leiden Open Variation Database | RCV000012825 | SCV001365295 | pathogenic | Fanconi anemia, complementation group C | 2020-02-28 | no assertion criteria provided | curation | Curator: Arleen D. Auerbach. Submitters to LOVD: Arleen D. Auerbach, Daniela Pilonetto. |