ClinVar Miner

Submissions for variant NM_000136.3(FANCC):c.67del (p.Asp23fs) (rs104886459)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 8
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Center for Pediatric Genomic Medicine,Children's Mercy Hospital and Clinics RCV000058926 SCV000280699 pathogenic not provided 2015-02-11 criteria provided, single submitter clinical testing
Counsyl RCV000012829 SCV000677956 pathogenic Fanconi anemia, complementation group C 2015-06-14 criteria provided, single submitter clinical testing
GeneDx RCV000058926 SCV000149267 pathogenic not provided 2018-07-16 criteria provided, single submitter clinical testing The pathogenic FANCC c.67delG deletion causes a frameshift, which changes an Aspartic Acid to an Isoleucine at codon 23, and creates a premature stop codon at position 23 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.67delG, previously reported as 322delG, has been reported as a founder variant in the Dutch population with approximately 50% of Dutch individuals with Fanconi Anemia being homozygous for this deletion (Whitney 1993, de Vries 2012, Gille 2012). Of note, the Fanconi Anemia patients that are homozygous or compound heterozygous for this deletion tend to have a mild presentation (Verlander 1994, de Vries 2012, Gille 2012). This variant has also been reported in the heterozygous state in at least three individuals with breast cancer (Berwick 2007, Thompson 2012). We consider this variant to be pathogenic.
GeneReviews RCV000012829 SCV000057810 pathogenic Fanconi anemia, complementation group C 2016-09-22 no assertion criteria provided literature only
Integrated Genetics/Laboratory Corporation of America RCV000012829 SCV000695436 pathogenic Fanconi anemia, complementation group C 2016-09-02 criteria provided, single submitter clinical testing Variant summary: The FANCC c.67delG (p.Asp23Ilefs) 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 was found in 8/121184 control chromosomes at a frequency of 0.000066, which does not exceed the estimated maximal expected allele frequency of a pathogenic FANCC variant (0.0017678). The variant is a common disease variant reported in numerous affected individuals in the literature in the homozygous and compound heterozygous state. It has been reported that individuals homozygous for the variant have milder phenotypes. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Invitae RCV000460906 SCV000549966 pathogenic Fanconi anemia 2018-12-30 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Asp23Ilefs*23) in the FANCC gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs104886459, ExAC 0.01%). This variant is a known common cause of Fanconi anemia, and is a recurrent variant in affected individuals of Dutch ancestry (PMID: 22778927, 22701786, 8128956, 9207444, 11110674, 20301575). In addition, this variant has been reported in the heterozygous state in individuals affected with breast cancer (PMID: 17909071, 23028338). This variant is also known as 322delG in the literature. ClinVar contains an entry for this variant (Variation ID: 12049). Experimental studies have shown that cells carrying this variant express an N terminal-truncated isoform of the FANCC protein, due to re-initiation of translation at a methionine (Met55) downstream of the premature translational stop signal (PMID: 27133164, 8639804). While this variant rescues inflammatory cytokine-induced cell death in vitro as efficiently as wild-type protein, it impairs FANCC-mediated nuclear DNA damage repair and therefore acts as a loss-of-function variant (PMID: 27133164, 8639804). Loss-of-function variants in FANCC are known to be pathogenic (PMID: 17924555). For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000012829 SCV000033069 pathogenic Fanconi anemia, complementation group C 2001-09-01 no assertion criteria provided literature only
SNPedia RCV000058926 SCV000090447 not provided not provided no assertion provided not provided

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.