Submissions for variant NM_000136.3(FANCC):c.705C>T (p.Pro235=)

gnomAD frequency: 0.00046  dbSNP: rs141828876

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000124964	SCV000168404	benign	not specified	2013-10-30	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	RCV000199490	SCV000253082	likely benign	Fanconi anemia	2024-01-29	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001095300	SCV000481133	uncertain significance	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, 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.
Ambry Genetics	RCV000564470	SCV000673307	likely benign	Hereditary cancer-predisposing syndrome	2017-01-25	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.
Genetic Services Laboratory, University of Chicago	RCV000124964	SCV002066520	likely benign	not specified	2020-09-18	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000124964	SCV002511388	likely benign	not specified	2022-04-28	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000199490	SCV002535118	likely benign	Fanconi anemia	2021-10-14	criteria provided, single submitter	curation
CeGaT Center for Human Genetics Tuebingen	RCV001195050	SCV004699731	likely benign	not provided	2024-01-01	criteria provided, single submitter	clinical testing	FANCC: BP4, BP7
PreventionGenetics, part of Exact Sciences	RCV003975106	SCV004790442	likely benign	FANCC-related disorder	2019-03-20	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).
Leiden Open Variation Database	RCV001195050	SCV001365321	uncertain significance	not provided	2020-02-28	no assertion criteria provided	curation	Curator: Arleen D. Auerbach. Submitter to LOVD: Arleen D. Auerbach.
Natera, Inc.	RCV001095300	SCV001463018	likely benign	Fanconi anemia complementation group C	2019-08-02	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001355936	SCV001550966	likely benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The FANCC p.Pro235= variant was not identified in the literature. The variant was identified in dbSNP (ID: rs141828876) as With other allele, ClinVar (classified as benign by GeneDx; classified as likely benign by Invitae, Ambry Genetics), and LOVD 3.0 (likely benign). The variant was identified in control databases in 88 of 277010 chromosomes at a frequency of 0.0003 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). It was observed in the following populations: African in 5 of 24014 chromosomes (freq: 0.0002), Other in 2 of 6468 chromosomes (freq: 0.0003), Latino in 3 of 34402 chromosomes (freq: 0.0001), European Non-Finnish in 78 of 126580 chromosomes (freq: 0.001); it was not observed in the Ashkenazi Jewish, East Asian, European Finnish, and South Asian populations. The p.Pro235= 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 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict 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.
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV001195050	SCV001809401	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001195050	SCV001965963	likely benign	not provided		no assertion criteria provided	clinical testing