Submissions for variant NM_000136.3(FANCC):c.1302dup (p.Gly435fs)

gnomAD frequency: 0.00002  dbSNP: rs730881709

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000160468	SCV000211033	pathogenic	not provided	2014-07-31	criteria provided, single submitter	clinical testing	This duplication of one nucleotide is denoted FANCC c.1302dupT at the cDNA level and p.Gly435TrpfsX83 (G435WfsX83) at the protein level. The normal sequence, with the bases that are duplicated in brackets, is GTGA[T]GGGA. The duplication causes a frameshift, which changes a Glycine to a Tryptophan at codon 435, and creates a premature stop codon at position 83 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 protein truncation. 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.
Invitae	RCV000203768	SCV000261171	pathogenic	Fanconi anemia	2023-10-24	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gly435Trpfs*83) in the FANCC gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 124 amino acid(s) of the FANCC protein. This variant is present in population databases (rs730881709, gnomAD 0.002%). This variant has not been reported in the literature in individuals affected with FANCC-related conditions. ClinVar contains an entry for this variant (Variation ID: 182467). This variant disrupts a region of the FANCC protein in which other variant(s) (p.Arg548* and p.Leu554*) have been determined to be pathogenic (PMID: 8103176, 8613549, 8829660, 8882868). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000984265	SCV001361109	likely pathogenic	Fanconi anemia complementation group C	2022-04-07	criteria provided, single submitter	clinical testing	Variant summary: FANCC c.1302dupT (p.Gly435TrpfsX83) 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. The variant allele was found at a frequency of 4e-06 in 250858 control chromosomes. c.1302dupT has been reported in the literature in at-least one individual referred for cancer panel testing (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. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Ambry Genetics	RCV002381527	SCV002695607	pathogenic	Hereditary cancer-predisposing syndrome	2023-06-27	criteria provided, single submitter	clinical testing	The c.1302dupT pathogenic mutation, located in coding exon 12 of the FANCC gene, results from a duplication of T at nucleotide position 1302, causing a translational frameshift with a predicted alternate stop codon (p.G435Wfs*83). 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.
Baylor Genetics	RCV000984265	SCV004196650	pathogenic	Fanconi anemia complementation group C	2023-10-19	criteria provided, single submitter	clinical testing
Counsyl	RCV000984265	SCV001132391	likely pathogenic	Fanconi anemia complementation group C	2015-04-24	no assertion criteria provided	clinical testing