ClinVar Miner

Submissions for variant NM_000136.3(FANCC):c.1333C>T (p.Gln445Ter) (rs1057516298)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000409733 SCV000485434 likely pathogenic Fanconi anemia, complementation group C 2015-12-11 criteria provided, single submitter clinical testing
GeneDx RCV000657572 SCV000779309 pathogenic not provided 2014-12-31 criteria provided, single submitter clinical testing This pathogenic variant is denoted FANCC c.1333C>T at the cDNA level and p.Gln445Ter (Q445X) at the protein level. The substitution creates a nonsense variant, which changes a Glutamine to a premature stop codon (CAG>TAG), and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. Although this variant has not, to our knowledge, been reported in the literature, it is considered pathogenic. 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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