ClinVar Miner

Submissions for variant NM_000136.3(FANCC):c.455dup (p.Asn152fs) (rs774170058)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000465895 SCV000549961 pathogenic Fanconi anemia 2019-10-09 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Asn152Lysfs*9) in the FANCC gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs774170058, ExAC 0.005%). This variant has been reported in an individual affected with Fanconi anemia (PMID: 16429406). ClinVar contains an entry for this variant (Variation ID: 409657). Loss-of-function variants in FANCC are known to be pathogenic (PMID: 17924555). For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV000482020 SCV000566026 pathogenic not provided 2015-03-25 criteria provided, single submitter clinical testing This duplication of one nucleotide in FANCC is denoted c.455dupA at the cDNA level and p.Asn152LysfsX9 (N152KfsX9) at the protein level. The normal sequence, with the base that is duplicated in brackets, is TAAAAA[A]TGTGAG. The duplication causes a frameshift, which changes an Asparagine to a Lysine at codon 152, and creates a premature stop codon at position 9 of the new reading frame. This variant is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. FANCC c.455dupA, previously reported as FANCC 455_456dupA and 450_451insA, has been observed in individuals with Fanconi Anemia (Yates 2006, Ameziane 2008). we consider this variant to be 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.
Integrated Genetics/Laboratory Corporation of America RCV000590358 SCV000695431 likely pathogenic Fanconi anemia, complementation group C 2016-05-13 criteria provided, single submitter clinical testing Variant summary: The FANCC c.455dupA (p.Asn152Lysfs) variant results in a premature termination codon, predicted to cause an extremely truncated protein of only 151 amino acids (vs. 557 residues in the wild-type sequence) or absent FANCC protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this variant have been reported in FA patients in the literature (HGMD: p.R185*, p.Q465*, and p.R548*). One in silico tool predicts a damaging outcome for this variant. This variant was found in 3/118162 control chromosomes at a frequency of 0.0000254, which does not exceed the estimated maximal expected allele frequency of a pathogenic FANCC variant (0.0017678). The variant was reported in at least two affected individuals in the literature along with a second pathogenic FANCC mutation. Taken together, this variant is classified as likely pathogenic.
Baylor Genetics RCV000590358 SCV001163629 pathogenic Fanconi anemia, complementation group C criteria provided, single submitter clinical testing
Ambry Genetics RCV001022696 SCV001184463 pathogenic Hereditary cancer-predisposing syndrome 2019-03-21 criteria provided, single submitter clinical testing Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)
Counsyl RCV000590358 SCV001132187 likely pathogenic Fanconi anemia, complementation group C 2015-06-03 no assertion criteria provided clinical testing
Leiden Open Variation Database RCV000590358 SCV001365294 pathogenic Fanconi anemia, complementation group C 2020-02-28 no assertion criteria provided curation Curator: Arleen D. Auerbach. Submitters to LOVD: Arleen D. Auerbach, Johan de Winter.

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