ClinVar Miner

Submissions for variant NM_000136.3(FANCC):c.1394A>G (p.Gln465Arg) (rs1800368)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 11
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000120970 SCV000168413 benign not specified 2014-01-08 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Genetic Services Laboratory, University of Chicago RCV000120970 SCV000247342 benign not specified 2018-08-14 criteria provided, single submitter clinical testing
Invitae RCV001082312 SCV000252621 benign Fanconi anemia 2020-12-05 criteria provided, single submitter clinical testing
Ambry Genetics RCV000574575 SCV000673295 likely benign Hereditary cancer-predisposing syndrome 2018-12-05 criteria provided, single submitter clinical testing In silico models in agreement (benign);Other data supporting benign classification;Other strong data supporting benign classification
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000590373 SCV000695425 benign not provided 2016-04-29 criteria provided, single submitter clinical testing Variant summary: The c.1394A>G variant affects a non-conserved nucleotide, resulting in amino acid change from Gln to Arg. 5/5 in-silico tools predict benign outcome for this variant. This variant is found in 120/120326 control chromosomes at a frequency of 0.0009973, predominantly observed in African subpopulation in ExAC with observed MAF of 1%. This frequency exceeds the maximal expected frequency of a pathogenic allele (0.0017678), suggesting this variant is likely a benign polymorphism especially for Africans. This variant has been reported in the literature (Gibson_1996) in both cohorts of affected and control individuals and was classified by authors as a polymorphism. One patients unaffected parent who was obligated heterozygous carrier was genotyped to be homozygote for this variant, further supporting the neutral effect of this variant. In addition, multiple clinical laboratory/reputable database classified this variant as benign/likely benign, without evidence to independently evaluate. Taken together, the variant was classified as Benign.
Mendelics RCV000988196 SCV001137833 likely benign Fanconi anemia, complementation group A 2019-05-28 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV001169818 SCV001332595 likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
ITMI RCV000120970 SCV000085138 not provided not specified 2013-09-19 no assertion provided reference population
Leiden Open Variation Database RCV000590373 SCV001365338 uncertain significance not provided 2020-02-28 no assertion criteria provided curation Curator: Arleen D. Auerbach. Submitter to LOVD: Arleen D. Auerbach.
Natera, Inc. RCV001169818 SCV001458894 likely benign Fanconi anemia, complementation group C 2020-04-12 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001357248 SCV001552663 benign Malignant tumor of breast no assertion criteria provided clinical testing The FANCC p.Gln465Arg variant was identified in 1 of 194 proband chromosomes (frequency: 0.01546) from individuals or families with Fanconi Anemia (Gibson_1996_8844212). In this study of Fanconi Anemia patients, the p.Gln465Arg variant was also found to be homozygous in an unaffected individual, and was classified by the authors as a polymorphism (Gibson_1996_8844212). The variant was also identified in dbSNP (ID: rs1800368) as “With other allele”, ClinVar (as benign by GeneDx, Invitae, and Laboratory Corporation of America, and as likely benign by Genetic Services Laboratory University of Chicago, and Ambry Genetics), Clinvitae (as in ClinVar), and LOVD 3.0 databases. The variant was not identified in Cosmic and MutDB databases. The variant was identified in control databases in 301 of 277086 chromosomes at a frequency of 0.001086 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 261 of 24026 chromosomes (freq: 0.01086), Other in 2 of 6458 chromosomes (freq: 0.00031), Latino in 25 of 34414 chromosomes (freq: 0.000726), European (Non-Finnish) in 4 of 126630 chromosomes (freq: 0.000032), and South Asian in 9 of 30764 chromosomes (freq: 0.000293), while the variant was not observed in the Ashkenazi Jewish, East Asian, and European (Finnish) populations. The p.Gln465 residue is not conserved in mammals and the variant amino acid Arginine (Arg) is present in Rhesus macaques, increasing the likelihood that this variant does not have clinical significance. In addition, 5/5 computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information this variant meets our laboratory's criteria to be classified as benign.

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.