Submissions for variant NM_000136.3(FANCC):c.609C>T (p.Leu203=)

gnomAD frequency: 0.00006  dbSNP: rs567226063

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000205246	SCV000259747	likely benign	Fanconi anemia	2024-01-22	criteria provided, single submitter	clinical testing
GeneDx	RCV001354745	SCV000520430	likely benign	not provided	2020-12-01	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 23028338, 21279724)
Ambry Genetics	RCV001024894	SCV001186986	likely benign	Hereditary cancer-predisposing syndrome	2019-03-08	criteria provided, single submitter	clinical testing	This alteration is classified as likely 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.
Illumina Laboratory Services, Illumina	RCV001165847	SCV001328095	uncertain significance	Fanconi anemia complementation group C	2018-01-12	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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000443939	SCV001363457	likely benign	not specified	2020-01-31	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000205246	SCV002535111	likely benign	Fanconi anemia	2021-12-08	criteria provided, single submitter	curation
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV001165847	SCV004017619	likely benign	Fanconi anemia complementation group C	2023-07-07	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV001354745	SCV004160163	likely benign	not provided	2022-11-01	criteria provided, single submitter	clinical testing	FANCC: BP4, BP7
Natera, Inc.	RCV001165847	SCV001458708	likely benign	Fanconi anemia complementation group C	2020-09-16	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001354745	SCV001549433	likely benign	not provided		no assertion criteria provided	clinical testing	The FANCC p.Leu203= variant was identified in 1 of 380 proband chromosomes (frequency: 0.003) from individuals or families with Esophageal Squamous Cell Carcinoma (Akbari Mohammadreza 2011). The variant was also identified in dbSNP (ID: rs567226063 as "With Likely benign allele"), and ClinVar (2x as likely benign by Invitae and GeneDx). The variant was not identified in Cosmic or LOVD 3.0. The variant was identified in control databases in 20 of 276800 chromosomes at a frequency of 0.00007 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Other in 2 of 6456 chromosomes (freq: 0.0003), Latino in 3 of 34386 chromosomes (freq: 0.00009), European in 9 of 126496 chromosomes (freq: 0.00007), and South Asian in 6 of 30688 chromosomes (freq: 0.0002), while the variant was not observed in the African, Ashkenazi Jewish, East Asian, or Finnish populations. The p.Leu203= 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, 5 of 5 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 the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.