ClinVar Miner

Submissions for variant NM_020937.4(FANCM):c.5832G>T (p.Leu1944Phe)

gnomAD frequency: 0.00012  dbSNP: rs201017015
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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000809180 SCV000949322 uncertain significance Fanconi anemia 2023-10-05 criteria provided, single submitter clinical testing This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 1944 of the FANCM protein (p.Leu1944Phe). This variant is present in population databases (rs201017015, 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: 653408). 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.
GeneDx RCV001664428 SCV001875344 uncertain significance not provided 2023-10-03 criteria provided, single submitter clinical testing In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with ovarian or breast cancer, but also in unaffected controls (Lu et al., 2015; Dicks et al., 2017; Dorling et al., 2021); This variant is associated with the following publications: (PMID: 28881617, 26689913, 33471991)
Genetic Services Laboratory, University of Chicago RCV001816879 SCV002070090 uncertain significance not specified 2020-01-13 criteria provided, single submitter clinical testing DNA sequence analysis of the FANCM gene demonstrated a sequence change, c.5832G>T, in exon 22 that results in an amino acid change, p.Leu1944Phe. This sequence change does not appear to have been previously described in patients with FANCM-related disorders and has been described in the gnomAD database with a frequency of 0.06% in Ashkenazi Jewish populations (dbSNP rs201017015). The p.Leu1944Phe change affects a moderately conserved amino acid residue located in a domain of the FANCM protein that is known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Leu1944Phe substitution. Due to the lack of functional studies, the clinical significance of the p.Leu1944Phe change remains unknown at this time.
Sema4, Sema4 RCV002259022 SCV002529888 uncertain significance Hereditary cancer-predisposing syndrome 2021-09-30 criteria provided, single submitter curation
Fulgent Genetics, Fulgent Genetics RCV002495113 SCV002804085 uncertain significance Spermatogenic failure 28; Premature ovarian failure 15 2022-01-05 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV001664428 SCV004218831 uncertain significance not provided 2023-06-10 criteria provided, single submitter clinical testing In the published literature, this variant has been reported in an unaffected control in a study of high grade serous ovarian cancer cases (PMID: 28881617 (2017)). Additionally, it has also been reported in individuals with breast cancer as well as in unaffected controls (PMIDs: 33471991 (2021), see also LOVD ( The frequency of this variant in the general population, 0.00058 (6/10366 chromosomes (Genome Aggregation Database,, is uninformative in the assessment of its pathogenicity. 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.
Mendelics RCV003492175 SCV004232592 likely benign Hereditary cancer 2024-01-23 criteria provided, single submitter clinical testing
CeGaT Center for Human Genetics Tuebingen RCV001664428 SCV004810981 uncertain significance not provided 2024-03-01 criteria provided, single submitter clinical testing

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