Submissions for variant NM_020937.4(FANCM):c.4708C>T (p.Arg1570Cys)

gnomAD frequency: 0.00006  dbSNP: rs139376041

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001036562	SCV001199932	uncertain significance	Fanconi anemia	2025-01-29	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 1570 of the FANCM protein (p.Arg1570Cys). This variant is present in population databases (rs139376041, gnomAD 0.06%). 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: 835630). 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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	RCV001819740	SCV002064143	uncertain significance	not provided	2024-03-12	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 breast cancer and also in controls (PMID: 33471991); This variant is associated with the following publications: (PMID: 33471991)
Sema4, Sema4	RCV002255606	SCV002529859	uncertain significance	Hereditary cancer-predisposing syndrome	2021-11-23	criteria provided, single submitter	curation
Fulgent Genetics, Fulgent Genetics	RCV002481857	SCV002777897	uncertain significance	Spermatogenic failure 28; Premature ovarian failure 15	2022-04-13	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001819740	SCV004218806	uncertain significance	not provided	2022-12-18	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.00056 (14/24844 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in individuals with breast cancer and unaffected controls (PMID: 33471991 (2021)). 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	RCV004536064	SCV004748641	uncertain significance	FANCM-related disorder	2023-11-25	no assertion criteria provided	clinical testing	The FANCM c.4708C>T variant is predicted to result in the amino acid substitution p.Arg1570Cys. This variant has been reported in both cases and controls within a breast cancer cohort (Dorling et al. 2021. PubMed ID: 33471991). This variant is reported in 0.056% of alleles in individuals of African descent in gnomAD and is interpreted as uncertain in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/835630/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.