Submissions for variant NM_020937.4(FANCM):c.4627C>T (p.Leu1543Phe)

gnomAD frequency: 0.00020  dbSNP: rs139536545

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000347988	SCV000950321	uncertain significance	Fanconi anemia	2024-01-25	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 1543 of the FANCM protein (p.Leu1543Phe). This variant is present in population databases (rs139536545, gnomAD 0.05%). This missense change has been observed in individual(s) with breast or ovarian cancer (PMID: 29351780). ClinVar contains an entry for this variant (Variation ID: 313220). 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.
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV001786361	SCV002011475	uncertain significance	not provided	2021-11-03	criteria provided, single submitter	clinical testing
GeneDx	RCV001786361	SCV002028740	uncertain significance	not provided	2023-06-05	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with breast or ovarian cancer (Dicks et al., 2017; Nguyen-Dumont et al., 2018); This variant is associated with the following publications: (PMID: 29351780, 28881617)
Genetic Services Laboratory, University of Chicago	RCV001820930	SCV002067658	uncertain significance	not specified	2020-12-24	criteria provided, single submitter	clinical testing	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 low population frequency of 0.022% (dbSNP rs139536545). The p.Leu1543Phe 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.Leu1543Phe substitution. Due to these contrasting evidences and the lack of functional studies, the clinical significance of the p.Leu1543Phe change remains unknown at this time.
Fulgent Genetics, Fulgent Genetics	RCV002487387	SCV002784817	uncertain significance	Spermatogenic failure 28; Premature ovarian failure 15	2022-03-29	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001786361	SCV004218805	uncertain significance	not provided	2023-09-01	criteria provided, single submitter	clinical testing	In the published literature, this variant has been reported in individuals with breast and/or ovarian cancer (PMID: 29351780 (2018)). This variant has also been reported in a child with acute lymphocytic leukemia (PMID: 26580448 (2015)). The frequency of this variant in the general population, 0.00056 (14/24972 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), 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.
PreventionGenetics, part of Exact Sciences	RCV003950067	SCV004763831	uncertain significance	FANCM-related condition	2023-12-31	criteria provided, single submitter	clinical testing	The FANCM c.4627C>T variant is predicted to result in the amino acid substitution p.Leu1543Phe. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.056% of alleles in individuals of European (Finnish) descent in gnomAD. This variant is interpreted as uncertain in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/313220/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.