Submissions for variant NM_020937.4(FANCM):c.5683T>C (p.Cys1895Arg)

gnomAD frequency: 0.00003  dbSNP: rs148945714

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000792201	SCV000931481	uncertain significance	Fanconi anemia	2024-01-23	criteria provided, single submitter	clinical testing	This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 1895 of the FANCM protein (p.Cys1895Arg). This variant is present in population databases (rs148945714, gnomAD 0.01%). 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: 639418). 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	RCV003238216	SCV002011468	uncertain significance	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002493442	SCV002780871	uncertain significance	Spermatogenic failure 28; Premature ovarian failure 15	2021-11-19	criteria provided, single submitter	clinical testing
GeneDx	RCV003238216	SCV003936191	uncertain significance	not provided	2024-11-11	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV003238216	SCV005626332	uncertain significance	not provided	2023-12-26	criteria provided, single submitter	clinical testing	The FANCM c.5683T>C (p.Cys1895Arg) variant has been identified in the published literature in individuals with breast cancer and other cancer types, including pancreatic cancer and acute myeloid leukemia, as well as in reportedly healthy individuals (PMIDs: 26483394 (2015), 32235514 (2020), 33471991 (2021), 34482403 (2022), 36707629 (2023), 37450374 (2023), see also LOVD (http://databases.lovd.nl/shared/genes/FANCM)). The frequency of this variant in the general population, 0.00017 (6/35424 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	RCV004738007	SCV005345020	uncertain significance	FANCM-related disorder	2024-08-28	no assertion criteria provided	clinical testing	The FANCM c.5683T>C variant is predicted to result in the amino acid substitution p.Cys1895Arg. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.017% of alleles in individuals of Latino descent in gnomAD and is reported as a variant of uncertain significance in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/639418/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.