Total submissions: 9
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Labcorp Genetics |
RCV000698336 | SCV000826996 | uncertain significance | Fanconi anemia | 2025-02-01 | 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 999 of the FANCM protein (p.Pro999Leu). This variant is present in population databases (rs148304968, gnomAD 0.1%). This missense change has been observed in individual(s) with colorectal cancer and breast cancer (PMID: 31428572, 36707629). ClinVar contains an entry for this variant (Variation ID: 575971). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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. |
Cancer Genomics Group, |
RCV001030481 | SCV001193589 | uncertain significance | Hereditary breast ovarian cancer syndrome | 2019-05-01 | criteria provided, single submitter | research | |
Gene |
RCV001662769 | SCV001874071 | uncertain significance | not provided | 2024-08-06 | criteria provided, single submitter | clinical testing | In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 32566746, 37646306, 33471991, 31428572, 26689913, 36534659) |
Genetic Services Laboratory, |
RCV001816721 | SCV002065682 | uncertain significance | not specified | 2021-08-24 | criteria provided, single submitter | clinical testing | DNA sequence analysis of the FANCM gene demonstrated a sequence change, c.2996C>T, in exon 14 that results in an amino acid change, p.Pro999Leu. This sequence change has been described in the gnomAD database with a frequency of 0.15% in the African/African-American subpopulation (dbSNP rs148304968). The p.Pro999Leu change affects a highly conserved amino acid residue located in a domain of the FANCM protein that is not known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Pro999Leu substitution. This sequence change does not appear to have been previously described in individuals with FANCM-related disorders. Due to insufficient evidences and the lack of functional studies, the clinical significance of the p.Pro999Leu change remains unknown at this time. |
Sema4, |
RCV002256479 | SCV002527344 | uncertain significance | Hereditary cancer-predisposing syndrome | 2021-08-19 | criteria provided, single submitter | curation | |
Fulgent Genetics, |
RCV002477590 | SCV002787365 | uncertain significance | Spermatogenic failure 28; Premature ovarian failure 15 | 2022-03-01 | criteria provided, single submitter | clinical testing | |
Ambry Genetics | RCV003243265 | SCV003940644 | uncertain significance | Inborn genetic diseases | 2023-04-27 | criteria provided, single submitter | clinical testing | The c.2996C>T (p.P999L) alteration is located in coding exon 14 of the FANCM gene. This alteration results from a C to T substitution at nucleotide position 2996, causing the proline (P) at amino acid position 999 to be replaced by a leucine (L). Based on data from gnomAD, the T allele has an overall frequency of 0.029% (81/281220) total alleles studied. The highest observed frequency was 0.146% (36/24630) of African alleles. This amino acid position is highly conserved in available vertebrate species. This alteration is predicted to be tolerated by in silico analysis. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. |
Neuberg Centre For Genomic Medicine, |
RCV003446359 | SCV004171923 | uncertain significance | Premature ovarian failure 15 | criteria provided, single submitter | clinical testing | ||
Quest Diagnostics Nichols Institute San Juan Capistrano | RCV001662769 | SCV004218755 | uncertain significance | not provided | 2024-05-10 | criteria provided, single submitter | clinical testing | The FANCM c.2996C>T (p.Pro999Leu) variant has been reported in the published literature in individuals with breast cancer (PMIDs: 33471991 (2021) and 36707629 (2023)), rectal cancer (PMID: 31428572 (2019)), myelodysplastic syndrome (PMID: 36534659 (2022)), angioimmunoblastic T-cell lymphoma (PMID: 37646306 (2023)), and reportedly healthy individuals (PMIDs: 33471991 (2021), 36707629 (2023), see also LOVD (http://databases.lovd.nl/shared/genes/FANCM)). The frequency of this variant in the general population, 0.0015 (36/24630 chromosomes in African/African American subpopulation (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is higher than would generally be expected for pathogenic variants in this gene. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is benign or damaging. Based on the available information, we are unable to determine the clinical significance of this variant. |