Submissions for variant NM_000136.3(FANCC):c.816C>T (p.Ile272=)

gnomAD frequency: 0.00074  dbSNP: rs55719336

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000124965	SCV000168405	benign	not specified	2014-05-15	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000203994	SCV000261270	benign	Fanconi anemia	2025-01-29	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001095299	SCV000481132	benign	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 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.
Genetic Services Laboratory, University of Chicago	RCV000124965	SCV000594673	likely benign	not specified	2016-05-27	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000563129	SCV000673310	likely benign	Hereditary cancer-predisposing syndrome	2016-09-29	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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000588252	SCV000695438	benign	not provided	2016-04-29	criteria provided, single submitter	clinical testing	Variant summary: The FANCC c.816C>T (p.Ile272Ile) variant affects a non-conserved nucleotide, resulting in a synonymous mutation. Mutation taster predicts damaging outcome for this variant while 5/5 in silico tools via Alamut predict the variant not to have an impact on normal splicing. The variant was observed by the ExAC project in 159/121094 control chromosomes (1 homozygote) at a frequency of 0.001313, which does not exceed maximal expected frequency of a pathogenic allele (0.0017678). However, in the East Asian subcohort, the variant was observed at an allele frequency of 0.015 which exceeds the estimated maximal expected allele frequency of a disease causing FANCC allele indicating the variant to be a neutral polymorphism in populations of East Asian origin. In addition, two independent clinical laboratory databases classified this variant as Benign via ClinVar (without evidence to independently evaluate). Considering the high prevalence of the variant in the East Asian population, it was classified as Benign.
CeGaT Center for Human Genetics Tuebingen	RCV000588252	SCV004811157	benign	not provided	2024-03-01	criteria provided, single submitter	clinical testing	FANCC: BP4, BP7, BS1, BS2
Leiden Open Variation Database	RCV000588252	SCV001365323	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	RCV000124965	SCV001554254	benign	not specified		no assertion criteria provided	clinical testing	The FANCC p.Ile272= variant was identified in 1 of 1038 proband chromosomes (frequency: 0.001) from individuals or families with pancreatic and breast cancers and was present in 1 of 1316 control chromosomes (frequency: 0.001) from healthy individuals (Couch 2005, Seal 2003). The variant was also identified in dbSNP (ID: rs55719336) as “with other allele”; in ClinVar and Clinvitae databases as benign by GeneDx and Invitae, and as uncertain significance by Illumina Clinical Serivices; and in LOVD 3.0 database with no classification provided. Furthermore, the variant was also identified in the 1000 Genomes Project in 20 of 5000 chromosomes (frequency: 0.004) and in the NHLBI GO Exome Sequencing Project in 9 of 4406 African American alleles. The variant was not identified in Cosmic and MutDB, databases. The variant was identified in control databases in 339 (4 homozygous) of 277168 chromosomes at a frequency of 0.001 in the following populations: African in 31 of 24028 chromosomes (freq. 0.001), Latino in 2 of 34412 chromosomes (freq. 0.00006), European Non-Finnish in 1 of 126670 chromosomes (freq. 0.00001), East Asian in 291 of 18864 chromosomes (freq. 0.02), South Asian in 10 of 30780 chromosomes (freq. 0.0003), and in other in 4 of 6468 chromosomes (freq. 0.001) but was not seen in Ashkenazi Jewish and European Finnish populations (Genome Aggregation Consortium Feb 27, 2017). The p.Ile272= 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.
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000124965	SCV001808969	benign	not specified		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000124965	SCV001926252	benign	not specified		no assertion criteria provided	clinical testing
Natera, Inc.	RCV000203994	SCV002081217	likely benign	Fanconi anemia	2017-06-13	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003905198	SCV004721175	benign	FANCC-related disorder	2019-11-19	no assertion criteria provided	clinical testing	This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).