Submissions for variant NM_000136.3(FANCC):c.*5C>T

gnomAD frequency: 0.00033  dbSNP: rs117175949

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000124976	SCV000168416	benign	not specified	2014-02-24	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.
Invitae	RCV000205839	SCV000260659	benign	Fanconi anemia	2015-09-16	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000576112	SCV000673315	benign	Hereditary cancer-predisposing syndrome	2017-01-04	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.
Illumina Laboratory Services, Illumina	RCV001167953	SCV001330504	likely benign	Fanconi anemia complementation group C	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Genetic Services Laboratory, University of Chicago	RCV000124976	SCV002068222	benign	not specified	2021-03-24	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV003457642	SCV004184797	benign	not provided	2024-01-01	criteria provided, single submitter	clinical testing	FANCC: BS1, BS2
Natera, Inc.	RCV000205839	SCV001190682	benign	Fanconi anemia	2019-05-20	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001357500	SCV001552986	benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The FANCC c.*5C>T variant was not identified in the literature nor was it identified in the LOVD 3.0 database. The variant was identified in dbSNP (ID: rs117175949) as "With Benign allele" and ClinVar (classified as benign by Invitae, GeneDx, and Ambry Genetics). The variant was identified in control databases in 256 of 276794 chromosomes (2 homozygous) at a frequency of 0.0009 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: East Asian in 225 of 18854 chromosomes (freq: 0.01, increasing the likelihood this could be a low frequency benign variant), Other in 2 of 6464 chromosomes (freq: 0.0003), Latino in 1 of 34408 chromosomes (freq: 0.00003), European in 9 of 126516 chromosomes (freq: 0.00007), and South Asian in 19 of 30746 chromosomes (freq: 0.0006); it was not observed in the African, Ashkenazi Jewish, or Finnish populations. The c.*5C>T variant is located 5 nucleotides downstream of the termination codon and 3 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict the creation of a cryptic splice site – although this finding is likely not relevant given the variant occurs downstream of the open reading frame. In summary, based on the above information, this variant meets our laboratory's criteria to be classified as benign.