Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Illumina Laboratory Services, |
RCV001148312 | SCV001309202 | uncertain significance | Fanconi anemia complementation group D2 | 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. |
| Genetic Services Laboratory, |
RCV001819855 | SCV002065224 | uncertain significance | not specified | 2021-04-16 | criteria provided, single submitter | clinical testing | DNA sequence analysis of the FANCD2 gene demonstrated a sequence change, c.2276C>T, in exon 25 that results in an amino acid change, p.Pro759Leu. This sequence change has been described in gnomAD with a population frequency of 0.0016% in the Non-Finnish European sub-population (dbSNP rs758628578). The p.Pro759Leu change affects a moderately conserved amino acid residue located in a domain of the FANCD2 protein that is not known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Pro759Leu substitution. This sequence change does not appear to have been previously described in patients with FANCD2-related disorders. Due to the lack of sufficient evidences, the clinical significance of the p.Pro759Leu change remains unknown at this time. |
| Fulgent Genetics, |
RCV001148312 | SCV002788377 | uncertain significance | Fanconi anemia complementation group D2 | 2021-10-19 | criteria provided, single submitter | clinical testing | |
| Labcorp Genetics |
RCV005093642 | SCV005830402 | uncertain significance | Fanconi anemia | 2024-08-29 | criteria provided, single submitter | clinical testing | This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 759 of the FANCD2 protein (p.Pro759Leu). This variant is present in population databases (rs758628578, gnomAD 0.007%). This variant has not been reported in the literature in individuals affected with FANCD2-related conditions. ClinVar contains an entry for this variant (Variation ID: 902058). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt FANCD2 protein function with a positive predictive value of 80%. 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. |