Submissions for variant NM_001018115.3(FANCD2):c.1278+5G>T

dbSNP: rs796652647

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV001151039	SCV001312138	uncertain significance	Fanconi anemia complementation group D2	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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003155362	SCV003844460	benign	not specified	2023-02-08	criteria provided, single submitter	clinical testing	Variant summary: FANCD2 c.1278+5G>T alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Three predict the variant abolishes a 5 prime splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.022 in 247256 control chromosomes (gnomAD and ALFA databases). The observed variant frequency is approximately 45 fold of the estimated maximal expected allele frequency for a pathogenic variant in FANCD2 causing Fanconi Anemia phenotype (0.00048), strongly suggesting that the variant is benign. c.1278+5G>T has been reported in the literature in individuals affected with anaplastic astrocytoma. This report does not provide unequivocal conclusions about association of the variant with Fanconi Anemia. Co-occurrences with a pathogenic variant has been reported (TP53 c.743G>A, p.Arg248Gln), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as benign.
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV001724256	SCV001952727	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001724256	SCV001964243	uncertain significance	not provided		no assertion criteria provided	clinical testing