ClinVar Miner

Submissions for variant NM_020937.4(FANCM):c.53G>A (p.Arg18Gln)

gnomAD frequency: 0.00011  dbSNP: rs146609069
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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000554625 SCV000626381 uncertain significance Fanconi anemia 2024-01-31 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 18 of the FANCM protein (p.Arg18Gln). This variant is present in population databases (rs146609069, gnomAD 0.05%). This variant has not been reported in the literature in individuals affected with FANCM-related conditions. ClinVar contains an entry for this variant (Variation ID: 456276). 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 tolerated. 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.
Fulgent Genetics, Fulgent Genetics RCV000763926 SCV000894870 uncertain significance Spermatogenic failure 28; Premature ovarian failure 15 2022-04-14 criteria provided, single submitter clinical testing
Mendelics RCV000989207 SCV001139436 likely benign Fanconi anemia complementation group A 2024-04-09 criteria provided, single submitter clinical testing
GeneDx RCV001770408 SCV002001437 uncertain significance not provided 2023-02-24 criteria provided, single submitter clinical testing In silico analysis supports that this missense variant does not alter protein structure/function; Observed in an individual with a personal history of high grade serous ovarian cancer in published literature (Dicks et al., 2017); This variant is associated with the following publications: (PMID: 28881617)
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden RCV001770408 SCV002011471 uncertain significance not provided 2021-11-03 criteria provided, single submitter clinical testing
Genetic Services Laboratory, University of Chicago RCV001821483 SCV002065685 uncertain significance not specified 2021-01-07 criteria provided, single submitter clinical testing DNA sequence analysis of the FANCM gene demonstrated a sequence change, c.53G>A, in exon 1 that results in an amino acid change, p.Arg18Gln. This sequence change does not appear to have been previously described in individuals with FANCM-related disorders and has been described in the gnomAD database with a frequency of 0.056% in the South Asian sub-population (dbSNP rs146609069). The p.Arg18Gln change affects a poorly 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.Arg18Gln substitution. Due to these contrasting evidences and the lack of functional studies, the clinical significance of the p.Arg18Gln change remains unknown at this time.
AiLife Diagnostics, AiLife Diagnostics RCV001770408 SCV002501233 uncertain significance not provided 2022-01-31 criteria provided, single submitter clinical testing
Neuberg Centre For Genomic Medicine, NCGM RCV003338648 SCV004048138 uncertain significance Premature ovarian failure 15 criteria provided, single submitter clinical testing The amino acid Arg at position 18 is changed to a Gln changing protein sequence and it might alter its composition and physico-chemical properties. The missense variant FANCM c.53G>A (p.Arg18Gln) has been submitted to ClinVar as a Variant of Uncertain Significance. The variant has not been reported in affected individuals. The p.Arg18Gln variant is observed with allele frequency (0.01351%) in gnomAD Exomes and is also reported in 1000 Genomes. The p.Arg18Gln missense variant is predicted to be tolerated by in silico tools. The amino acid change p.Arg18Gln in FANCM is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Uncertain Significance.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV001770408 SCV004218821 uncertain significance not provided 2023-03-02 criteria provided, single submitter clinical testing The frequency of this variant in the general population, 0.00056 (17/30614 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in affected individuals with breast cancer as well as in a control individuals in a large scale breast cancer association study (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/FANCM)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant.
Breakthrough Genomics, Breakthrough Genomics RCV001770408 SCV005192305 uncertain significance not provided criteria provided, single submitter not provided

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