Submissions for variant NM_000136.3(FANCC):c.843+4C>T

gnomAD frequency: 0.01468  dbSNP: rs4647506

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000206886	SCV000261884	benign	Fanconi anemia	2024-02-01	criteria provided, single submitter	clinical testing
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000224721	SCV000281296	likely benign	not provided	2015-09-28	criteria provided, single submitter	clinical testing	Converted during submission to Likely benign.
Illumina Laboratory Services, Illumina	RCV001095298	SCV000481131	benign	Fanconi anemia complementation group C	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Ambry Genetics	RCV000568730	SCV000673291	benign	Hereditary cancer-predisposing syndrome	2016-08-18	criteria provided, single submitter	clinical testing	This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000224721	SCV000695439	benign	not provided	2016-04-29	criteria provided, single submitter	clinical testing	Variant summary: The FANCC c.843+4C>T variant affects a non-conserved intronic nucleotide. Mutation Taster predicts a damaging outcome for this intronic variant, but 5/5 Alamut algorithms predict no significant change to the splice donor site. However, this variant has not been evaluated for functional impact by in vivo/vitro studies. This variant was found in 504/121048 control chromosomes (6 homozygotes) at a frequency of 0.0041636. The variant is observed primarily in the African subpopulation at a frequency of 4.5%, which is about 25 times the maximal expected frequency of a pathogenic FANCC allele (0.0017678), strong evidence that this variant is benign. The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases/clinical laboratories. In addition, a clinical laboratory classified this variant as benign. Taken together, this variant was classified as benign.
GeneDx	RCV000224721	SCV001846376	benign	not provided	2015-03-03	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001729458	SCV002774534	benign	not specified	2021-06-23	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV001095298	SCV002798959	likely benign	Fanconi anemia complementation group C	2022-05-01	criteria provided, single submitter	clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV001095298	SCV004017609	benign	Fanconi anemia complementation group C	2023-07-07	criteria provided, single submitter	clinical testing
Breakthrough Genomics, Breakthrough Genomics	RCV000224721	SCV005222437	likely benign	not provided		criteria provided, single submitter	not provided
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001356265	SCV001551382	benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The FANCC c.843+4C>T variant was not identified in the literature nor was it identified in the Cosmic, MutDB, or LOVD 3.0 databases. The variant was identified in dbSNP (ID: rs4647506) as “With other allele”, ClinVar (as benign by Invitae, Ambry Genetics, and Laboratory Corporation of America, and as likely benign by Center for Pediatric Genomic Medicine and Illumina), and Clinvitae (as in ClinVar) databases. The variant was identified in control databases in 1227 of 277134 chromosomes (28 homozygous) at a frequency of 0.004427 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include African in 1107 of 24010 chromosomes (freq: 0.04611), Other in 12 of 6468 chromosomes (freq: 0.001855), Latino in 80 of 34414 chromosomes (freq: 0.002325), European (Non-Finnish) in 17 of 126670 chromosomes (freq: 0.000134), and South Asian in 11 of 30772 chromosomes (freq: 0.000358), while the variant was not observed in the Ashkenazi Jewish, East Asian, or European (Finnish) populations. The c.843+4C>T variant is located in the 5' splice region but does not affect the invariant +1 and +2 positions. However, positions +3 to +6 are part of the splicing consensus sequence and variants involving these positions sometimes affect splicing. 1 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information this variant meets our laboratory's criteria to be classified as benign.
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV001729458	SCV001977762	benign	not specified		no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000224721	SCV001979913	likely benign	not provided		no assertion criteria provided	clinical testing
Natera, Inc.	RCV000206886	SCV002081212	benign	Fanconi anemia	2017-08-09	no assertion criteria provided	clinical testing