Submissions for variant NM_000136.3(FANCC):c.1425A>G (p.Thr475=)

gnomAD frequency: 0.00005  dbSNP: rs199739450

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV001537821	SCV000279395	likely benign	not provided	2018-09-10	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000566153	SCV000673316	likely benign	Hereditary cancer-predisposing syndrome	2017-02-23	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.
Invitae	RCV000630987	SCV000751964	likely benign	Fanconi anemia	2024-01-24	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000216583	SCV001363454	likely benign	not specified	2019-12-31	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003919895	SCV004729963	likely benign	FANCC-related disorder	2023-03-16	criteria provided, single submitter	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
Natera, Inc.	RCV001273978	SCV001457639	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	RCV001357238	SCV001552647	likely benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The FANCC p.Thr475= variant was not identified in the literature nor was it identified in the LOVD 3.0 database. The variant was identified in dbSNP (ID: rs199739450) as "With Likely benign allele" and ClinVar (classified as likely benign by Invitae, GeneDx and Ambry Genetics). The variant was identified in control databases in 68 of 277156 chromosomes at a frequency of 0.0003 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the Latino population in 68 of 34418 chromosomes (freq: 0.002), while the variant was not observed in the African, Other, European, Ashkenazi Jewish, East Asian, Finnish, and South Asian populations. The p.Thr475= 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. The variant occurs outside of the splicing consensus sequence and 1 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predicts a greater than 10% difference in splicing; this is not very predictive of pathogenicity. 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.