Submissions for variant NM_000136.3(FANCC):c.584A>T (p.Asp195Val) (rs1800365)

Total submissions: 23

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000120978	SCV000168402	benign	not specified	2013-10-17	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.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics	RCV000120978	SCV000232007	benign	not specified	2015-08-24	criteria provided, single submitter	clinical testing
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics,Children's Hospital of Philadelphia	RCV000120978	SCV000257632	uncertain significance	not specified	2015-07-01	criteria provided, single submitter	clinical testing
Invitae	RCV001083500	SCV000261219	benign	Fanconi anemia	2020-12-04	criteria provided, single submitter	clinical testing
Vantari Genetics	RCV000124962	SCV000267037	benign	Hereditary cancer-predisposing syndrome	2015-12-03	criteria provided, single submitter	clinical testing
Center for Pediatric Genomic Medicine,Children's Mercy Hospital and Clinics	RCV000179716	SCV000281279	likely benign	not provided	2015-08-26	criteria provided, single submitter	clinical testing	Converted during submission to Likely benign.
PreventionGenetics,PreventionGenetics	RCV000120978	SCV000302521	likely benign	not specified		criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine	RCV000120978	SCV000539136	likely benign	not specified	2016-03-28	criteria provided, single submitter	clinical testing	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Reported in 1 proband of European ancestry in homozygous state (Verlander 1994). Classified as Benign in ClinVar by GeneDx. MAF 0.4%.
Genetic Services Laboratory, University of Chicago	RCV000120978	SCV000594678	likely benign	not specified	2015-09-29	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000124962	SCV000673285	benign	Hereditary cancer-predisposing syndrome	2018-09-21	criteria provided, single submitter	clinical testing	In silico models in agreement (deleterious) and/or completely conserved position in appropriate species;Intact protein function observed by in vitro/ex vivo assays;Intact protein function observed in appropriate functional assay(s);Seen in trans with a mutation or in homozygous state in individual without severe disease for that gene;Sub-population frequency in support of benign classification (not ava blue, manual h-w);Subpopulation frequency in support of benign classification
Counsyl	RCV000667368	SCV000791802	likely benign	Fanconi anemia, complementation group C	2017-05-25	criteria provided, single submitter	clinical testing
Mendelics	RCV000667368	SCV000838354	likely benign	Fanconi anemia, complementation group C	2018-07-02	criteria provided, single submitter	clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen	RCV000179716	SCV000892896	uncertain significance	not provided	2018-06-01	criteria provided, single submitter	clinical testing
Mendelics	RCV000988215	SCV001137852	likely benign	Fanconi anemia, complementation group A	2019-05-28	criteria provided, single submitter	clinical testing
Illumina Clinical Services Laboratory,Illumina	RCV000667368	SCV001329919	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). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Baylor Genetics	RCV000667368	SCV001522905	uncertain significance	Fanconi anemia, complementation group C	2019-05-29	criteria provided, single submitter	clinical testing	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Nilou-Genome Lab	RCV000667368	SCV001653385	likely benign	Fanconi anemia, complementation group C	2021-05-18	criteria provided, single submitter	clinical testing
ITMI	RCV000120978	SCV000085146	not provided	not specified	2013-09-19	no assertion provided	reference population
Leiden Open Variation Database	RCV000179716	SCV001365302	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	RCV001356570	SCV001551778	likely benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The FANCC p.Asp195Val variant was identified in 2 of 436 proband chromosomes (frequency: 0.005) from individuals or families of northern or eastern European and southern Italian descent with pancreatic cancer and Fanconi Anemia (Verlander 1994, Van Der Heijden 2003). The variant was also identified in the following databases: dbSNP (ID: rs1800365), in the ClinVar database as benign by GeneDx, Emory Genetics, Invitae, Vantari Genetics; as likely benign by Centre for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics, Prevention Genetics and Laboratory for Molecular Medicine, Partners Health Care Personalized Medicine; and as uncertain significance by Division of Genomic Diagnostics, Children's Hospital of Philadelphia Study Description: and in Clinvitae database as benign by Emyclass. The variant was also listed in the LOVD 3.0 database; however no relevant information was given. The variant was not identified in Cosmic and MutDB. In addition, the variant was identified in the 1000 Genomes Project in 13 of 5000 chromosomes (frequency: 0.003) and the NHLBI GO Exome Sequencing Project in 40 of 8600 European American and in 4 of 4406 African American alleles. The variant was identified in control databases in 842 (4 homozygous) of 277070 chromosomes at a frequency of 0.003 increasing the likelihood this could be a low frequency variant (Genome Aggregation Consortium Feb 27, 2017). Breakdown of observations by population is: European (Non-Finnish) in 568 (3 homozygous) of 126606 chromosomes (freq: 0.004), Ashkenazi Jewish in 36 of 10144 chromosomes (freq: 0.004), South Asian in 107 of 30766 chromosomes (freq: 0.003), Latino in 95 (1 homozygous) of 34412 chromosomes (freq: 0.003), Other in 16 of 6456 chromosomes (freq: 0.001), African in 12 of 24028 chromosomes (freq: 0.0005), and European (Finnish) in 8 of 25788 chromosomes (freq: 0.0003), while not observed in the East Asian population. The p.Asp195 residue is conserved in in mammals but not in more distantly related organisms and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the p.Asp195Val variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. The variant is located with the Fanconi anaemia group C protein functional domain. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we lean towards a more benign role for this variant. This variant is classified as likely benign.
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000179716	SCV001807888	likely benign	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000120978	SCV001927745	benign	not specified		no assertion criteria provided	clinical testing
Human Genetics - Radboudumc,Radboudumc	RCV000120978	SCV001957656	benign	not specified		no assertion criteria provided	clinical testing