ClinVar Miner

Submissions for variant NM_000136.3(FANCC):c.1385_1386TC[1] (p.Ala464fs) (rs730881710)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000160469 SCV000211034 pathogenic not provided 2014-09-08 criteria provided, single submitter clinical testing This deletion of 2 nucleotides in FANCC is denoted c.1387_1388delTC at the cDNA level and p.Ala464ProfsX53 (A464PfsX53) at the protein level. The normal sequence, with the bases that are deleted in brackets, is CCTC[TC]AGCC. The deletion causes a frameshift, which changes an Alanine to a Proline at codon 464, and creates a premature stop codon at position 53 of the new reading frame. Although this variant has not, to our knowledge, been reported in the literature, it is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. 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.
Counsyl RCV000672163 SCV000797239 likely pathogenic Fanconi anemia, complementation group C 2018-01-19 criteria provided, single submitter clinical testing
Invitae RCV000798003 SCV000937595 pathogenic Fanconi anemia 2018-10-26 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the FANCC gene (p.Ala464Profs*53). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 95 amino acids of the FANCC protein. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has been observed in an individual affected with breast cancer (PMID: 26681312). ClinVar contains an entry for this variant (Variation ID: 182468). Experimental studies and prediction algorithms are not available for this variant, and the functional significance of the affected amino acid(s) is currently unknown. This variant disrupts the C-terminus of the FANCC protein. Other variant(s) that disrupt this region (p.Arg548*) have been determined to be pathogenic (PMID: 8103176, 8844212, 24584348). This suggests that variants that disrupt this region of the protein are likely to be causative of disease. For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV001011210 SCV001171507 pathogenic Hereditary cancer-predisposing syndrome 2019-06-13 criteria provided, single submitter clinical testing Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)

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