Submissions for variant NM_000136.3(FANCC):c.1387_1388del (p.Ala464fs)

dbSNP: rs730881710

Total submissions: 4

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	2023-11-05	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Ala464Profs*53) in the FANCC gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 95 amino acid(s) of the FANCC protein. This variant is present in population databases (rs730881710, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with breast cancer (PMID: 26681312). ClinVar contains an entry for this variant (Variation ID: 182468). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. This variant disrupts a region of the FANCC protein in which other variant(s) (p.Arg548*) have been determined to be pathogenic (PMID: 8103176, 8844212, 24584348). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. 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	The c.1387_1388delTC pathogenic mutation, located in coding exon 13 of the FANCC gene, results from a deletion of two nucleotides at nucleotide positions 1387 to 1388, causing a translational frameshift with a predicted alternate stop codon (p.A464Pfs*53). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.