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

Total submissions: 11

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.