Submissions for variant NM_000136.3(FANCC):c.319C>T (p.Gln107Ter)

dbSNP: rs730881731

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000160499	SCV000211064	pathogenic	not provided	2014-09-10	criteria provided, single submitter	clinical testing	This pathogenic variant is denoted FANCC c.319C>T at the cDNA level and p.Gln107Ter (Q107X) at the protein level. The substitution creates a nonsense variant, which changes a Glutamine to a premature stop codon (CAA>TAA), 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.
Invitae	RCV000472455	SCV000549962	pathogenic	Fanconi anemia	2016-07-02	criteria provided, single submitter	clinical testing	Loss-of-function variants in FANCC are known to be pathogenic.  This particular variant has been reported in the literature in an individual affected with breast cancer (PMID: 26681312). For these reasons, this variant has been classified as Pathogenic. This sequence change creates a premature translational stop signal at codon 107 (p.Gln107*) of the FANCC gene. It is expected to result in an absent or disrupted protein product.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000781350	SCV000919320	likely pathogenic	Fanconi anemia complementation group C	2018-08-20	criteria provided, single submitter	clinical testing	Variant summary: FANCC c.319C>T (p.Gln107X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (eg. c.553C>T (p.Arg185X) and c.1642C>T (p.Arg548X)). The variant was absent in 245972 control chromosomes (gnomAD). The variant, c.319C>T, has been reported in the literature in an individual affected with Breast Cancer (Susswein_2016). This report does not provide unequivocal conclusions about association of the variant with Fanconi Anemia Group C. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. A ClinVar submission from a clinical diagnostic laboratory (evaluation after 2014) cites the variant as "pathogenic." Based on the evidence outlined above, the variant was classified as likely pathogenic.