ClinVar Miner

Submissions for variant NM_000136.3(FANCC):c.843+4C>T (rs4647506)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000206886 SCV000261884 benign Fanconi anemia 2020-12-06 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 Clinical Services Laboratory,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: 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
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.

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