Submissions for variant NM_021922.3(FANCE):c.977T>G (p.Leu326Trp)

gnomAD frequency: 0.00001  dbSNP: rs779336261

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV001041144	SCV000462667	uncertain significance	Fanconi anemia complementation group E	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.
Invitae	RCV001041144	SCV001204744	uncertain significance	Fanconi anemia complementation group E	2022-09-20	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with tryptophan, which is neutral and slightly polar, at codon 326 of the FANCE protein (p.Leu326Trp). This variant is present in population databases (rs779336261, gnomAD 0.1%). This variant has not been reported in the literature in individuals affected with FANCE-related conditions. ClinVar contains an entry for this variant (Variation ID: 356449). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt FANCE protein function. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Sema4, Sema4	RCV002255375	SCV002527975	uncertain significance	Fanconi anemia	2021-11-26	criteria provided, single submitter	curation
Fulgent Genetics, Fulgent Genetics	RCV001041144	SCV002782258	uncertain significance	Fanconi anemia complementation group E	2021-12-31	criteria provided, single submitter	clinical testing
Laboratory of Molecular Epidemiology of Birth Defects, West China Second University Hospital, Sichuan University	RCV003153564	SCV003843796	likely pathogenic	Ovarian cancer	2022-01-01	criteria provided, single submitter	clinical testing