Submissions for variant NM_000136.3(FANCC):c.408A>G (p.Gln136=)

gnomAD frequency: 0.02397  dbSNP: rs1800360

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
PreventionGenetics, part of Exact Sciences	RCV000241551	SCV000302519	benign	not specified		criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001095333	SCV000481136	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000396417	SCV000560625	benign	Fanconi anemia	2024-02-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000569297	SCV000673294	benign	Hereditary cancer-predisposing syndrome	2016-08-29	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	RCV000588429	SCV000695424	benign	not provided	2016-04-29	criteria provided, single submitter	clinical testing	Variant summary: The FANCC c.408A>G variant affects a non-conserved nucleotide, resulting in a synonymous change. Mutation Taster predicts a benign outcome for this variant, and 5/5 Alamut algorithms predict no significant change to splicing. This variant was found in 807/120880 control chromosomes (36 homozygotes) at a frequency of 0.006676, which is about 4 times the maximal expected frequency of a pathogenic FANCC allele (0.0017678), suggesting 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; nor evaluated for functional impact by in vivo/vitro studies. Taken together, this variant was classified as benign.
GeneDx	RCV000588429	SCV001758927	benign	not provided	2015-03-03	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000241551	SCV002046962	benign	not specified	2021-04-20	criteria provided, single submitter	clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV001095333	SCV004017612	benign	Fanconi anemia complementation group C	2023-07-07	criteria provided, single submitter	clinical testing
Breakthrough Genomics, Breakthrough Genomics	RCV000588429	SCV005272094	benign	not provided		criteria provided, single submitter	not provided
Leiden Open Variation Database	RCV000588429	SCV001365292	uncertain significance	not provided	2020-02-28	no assertion criteria provided	curation	Curator: Arleen D. Auerbach. Submitter to LOVD: Arleen D. Auerbach.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001357182	SCV001552561	benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The FANCC p.Gln136= variant was identified in dbSNP (ID: rs1800360) as “With other allele” and in control databases in 2016 (87 homozygous) of 276974 chromosomes at a frequency of 0.007 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 1891 (87 homozygous) of 24020 chromosomes (freq: 0.08), Other in 17 of 6456 chromosomes (freq: 0.003), Latino in 94 of 34404 chromosomes (freq: 0.003), European Non-Finnish in 11 of 126548 chromosomes (freq: 0.00009), and South Asian in 3 of 30774 chromosomes (freq: 0.0001), while the variant was not observed in the Ashkenazi Jewish, East Asian, and European Finnish populations. The p.Gln136= variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. In addition, 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.
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000588429	SCV001800732	likely benign	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000241551	SCV001806840	benign	not specified		no assertion criteria provided	clinical testing
Natera, Inc.	RCV000396417	SCV002081276	benign	Fanconi anemia	2017-05-10	no assertion criteria provided	clinical testing