Submissions for variant NM_000136.3(FANCC):c.535C>T (p.Arg179Ter)

gnomAD frequency: 0.00001  dbSNP: rs769039987

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000224844	SCV000281191	likely pathogenic	not provided	2016-04-29	criteria provided, single submitter	clinical testing
GeneDx	RCV000224844	SCV000568699	likely pathogenic	not provided	2016-09-02	criteria provided, single submitter	clinical testing	This variant is denoted FANCC c.535C>T at the cDNA level and p.Arg179Ter (R179X) at the protein level. The substitution creates a nonsense variant, which changes an Arginine to a premature stop codon (CGA>TGA), and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. This variant was identified in a mother and daughter with ovarian and breast cancer respectively, but was absent in a second daughter who also had breast cancer (Thompson 2012). Based on currently available information, we consider this variant to be likely pathogenic.
Invitae	RCV000704130	SCV000833067	pathogenic	Fanconi anemia	2023-11-27	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg179*) in the FANCC gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in FANCC are known to be pathogenic (PMID: 17924555). This variant is present in population databases (rs769039987, gnomAD 0.002%). This premature translational stop signal has been observed in individual(s) with familial breast cancer and ovarian cancer (PMID: 23028338, 26990548). ClinVar contains an entry for this variant (Variation ID: 235535). For these reasons, this variant has been classified as Pathogenic.
Eurofins Ntd Llc (ga)	RCV000224844	SCV000861684	likely pathogenic	not provided	2018-06-04	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV001023972	SCV001185918	pathogenic	Hereditary cancer-predisposing syndrome	2022-05-05	criteria provided, single submitter	clinical testing	The p.R179* pathogenic mutation (also known as c.535C>T), located in coding exon 6 of the FANCC gene, results from a C to T substitution at nucleotide position 535. This changes the amino acid from an arginine to a stop codon within coding exon 6. This mutation has been reported in a proband with breast cancer diagnosed at 37 years and her mother with ovarian cancer diagnosed at 66 years; the mutation was not identified in the proband's sister with breast cancer diagnosed at 46 years (Thompson ER et al. PLoS Genet. 2012 Sep;8(9):e1002894). This mutation was also identified in an individual undergoing reproductive carrier screening (Abuli A et al. Hum. Mutat. 2016 06;37(6):516-23). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition to the clinical data in the literature, 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.
Revvity Omics, Revvity	RCV000984264	SCV002022324	pathogenic	Fanconi anemia complementation group C	2019-02-19	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000984264	SCV002809897	pathogenic	Fanconi anemia complementation group C	2021-12-29	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000984264	SCV004196679	pathogenic	Fanconi anemia complementation group C	2023-04-03	criteria provided, single submitter	clinical testing
Counsyl	RCV000984264	SCV001132390	likely pathogenic	Fanconi anemia complementation group C	2014-11-19	no assertion criteria provided	clinical testing