ClinVar Miner

Submissions for variant NM_000136.3(FANCC):c.896+2T>G (rs863224441)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000196695 SCV000253676 likely pathogenic Fanconi anemia 2015-04-17 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 9. It is expected to disrupt mRNA splicing and likely results in an absent or disrupted protein product. While this particular variant has not been reported in the literature, donor/acceptor splice site variants have been reported in FANCC (PMID: 20869034, 17924555) and truncating variants in FANCC are known to be pathogenic (PMID: 17924555). For these reasons, this variant has been classified as Likely Pathogenic.
GeneDx RCV000487051 SCV000564977 pathogenic not provided 2014-10-23 criteria provided, single submitter clinical testing This pathogenic variant is denoted FANCC c.896+2 T>G or IVS9+2 T>G and consists of a T>G nucleotide substitution at the +2 position of intron 9 of the FANCC gene. The variant destroys a canonical splice donor site and is predicted to cause abnormal gene splicing, leading to either an abnormal message that is subject to nonsense-mediated mRNA decay or to an abnormal protein product. While this variant has not, to our knowledge, been published in the literature, it is considered to be a pathogenic variant. FANCC has been only recently described in association with cancer predisposition and the risks are not well understood. Based on available data, the presence of a FANCC mutation may confer an increased risk for female breast cancer (Thompson 2012, Berwick 2007). Berwick et al. (2007) identified 33 female FANCC mutation carriers; all grandmothers of known Fanconi Anemia patients. In this group of women the observed cases of breast cancer (n=6) was significantly higher than the expected cases of breast cancer (SIR = 2.4). Thompson et al. (2012) studied 438 BRCA-negative breast cancer families and identified 3 families with deleterious FANCC mutations. In two of these families, the identified truncating FANCC mutations were found in multiple affected family members. The authors conclude that the co-segregation of FANCC mutations in these families appears to be consistent with moderately penetrant breast cancer alleles. Fanconi Anemia (FA) is a rare autosomal recessive condition that can be caused by two mutations (one affecting each allele) in the FANCC gene. This condition is characterized by an increased risk for childhood malignancy including leukemia and solid tumors, as well as distinctive physical abnormalities and bone marrow failure. If a FANCC mutation carrier'spartner is also a carrier for a FANCC mutation, the risk to have a child with FA is 25% with each pregnancy.

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