ClinVar Miner

Submissions for variant NM_000136.3(FANCC):c.355_360delinsA (p.Ser119fs) (rs587779904)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000115350 SCV000149259 pathogenic not provided 2017-07-05 criteria provided, single submitter clinical testing This combined deletion and insertion is denoted FANCC c.355_360delTCTCATinsA at the cDNA level and p.Ser119AsnfsX8 (S119NfsX8) at the protein level. The surrounding sequence is ATTA[delTCTCAT][insA]ATAC. The variant causes a frameshift which changes a Serine to an Asparagine at codon 119, and creates a premature stop codon at position 8 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.355_360delTCTCATinsA has been observed in at least three women with personal and family history of breast cancer (Frey 2017). Additionally, a similar FANCC variant, c.356_360delCTCAT, which results in the same frameshift, was observed in the homozygous state in a patient with Fanconi Anemia (Ameziane 2008). Based on currently available evidence, we consider FANCC c.355_360delTCTCATinsA to be pathogenic.
Invitae RCV000229758 SCV000283591 pathogenic Fanconi anemia 2017-06-26 criteria provided, single submitter clinical testing This sequence change deletes 6 nucleotides and inserts 1 nucleotide in exon 5 of the FANCC mRNA (c.355_360delTCTCATinsA), causing a frameshift at codon 119. This creates a premature translational stop signal (p.Ser119Asnfs*8) and is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals affected with breast cancer (PMID: 26681312). ClinVar contains an entry for this variant (Variation ID: 127540). Additionally, a similar variant (c.356_360del, p.Ser119Tyrfs*8) has been reported in an individual affected with Fanconi anemia (PMID: 17924555). Loss-of-function variants in FANCC are known to be pathogenic (PMID: 17924555). For these reasons, this variant has been classified as Pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV000590237 SCV000695428 likely pathogenic Fanconi anemia, complementation group C 2016-10-14 criteria provided, single submitter clinical testing Variant summary: The FANCC c.355_360delinsA (p.Ser119Asnfs) variant results in a premature termination codon, predicted to cause a truncated or absent FANCC protein due to nonsense mediated decay, which are commonly known mechanisms for disease. One in silico tool predicts a damaging outcome for this variant. This variant is absent in 119306 control chromosomes. The variant has been reported in BrC patients in the literature, and in one case the individual also carried a pathogenic BRCA2 variant. The variant of interest has not, to our knowledge, been reported in FA-C patients in the literature, however a similar variant (c.356_360del) has been reported in an affected individual in the homozygous state (Ameziane_2008). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as likely pathogenic.

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