ClinVar Miner

Submissions for variant NM_000136.3(FANCC):c.1302dup (p.Gly435fs) (rs730881709)

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Total submissions: 4
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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 2020-09-13 criteria provided, single submitter clinical testing This sequence change inserts 1 nucleotide in exon 13 of the FANCC mRNA (c.1302dupT), causing a frameshift at codon 435. This creates a premature translational stop signal in the last exon of the FANCC mRNA (p.Gly435Trpfs*83). While this is not anticipated to result in nonsense mediated decay, it is expected to result in a truncated FANCC protein. While this particular variant has not been reported in the literature, truncating variants located in the last exon of FANCC are known to be pathogenic (PMID: 8103176, 8829660, 8882868, 8613549). ClinVar contains an entry for this variant (Variation ID: 182467). Experimental studies have shown that nonsense variants p.Arg548* and p.Leu554*, both located downstream of the premature stop codon created by this variant, disrupt the functional activity of the FANCC protein, rendering it unable to complement mitomycin C hypersensitivity of cells in vitro (PMID: 8882868). In summary, this variant produces a frameshift that leads to a premature stop codon 83 amino acids downstream in the last exon of FANCC. While the transcript produced may escape nonsense mediated decay, functional studies have shown that the very C-terminal amino acids in the FANCC protein, which are removed by the c.1302dupT variant, are critical for proper protein function. 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 2019-12-26 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. Two 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 (n=1)/likely pathogenic(n=1). Based on the evidence outlined above, the variant was classified as likely pathogenic.
Counsyl RCV000984265 SCV001132391 likely pathogenic Fanconi anemia, complementation group C 2015-04-24 no assertion criteria provided clinical testing

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