Submissions for variant NM_020937.4(FANCM):c.1597C>T (p.Arg533Cys)

gnomAD frequency: 0.00029  dbSNP: rs146151355

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000820891	SCV000961625	uncertain significance	Fanconi anemia	2024-02-01	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 533 of the FANCM protein (p.Arg533Cys). This variant is present in population databases (rs146151355, gnomAD 0.06%). This missense change has been observed in individual(s) with breast cancer (PMID: 26094658). ClinVar contains an entry for this variant (Variation ID: 663092). 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	RCV001574713	SCV001801580	uncertain significance	not provided	2024-06-10	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 a personal or family history of breast, sarcoma, ovarian, prostate, or colorectal cancer, but also in unaffected controls (PMID: 26094658, 27498913, 27713038, 28881617, 32268276); This variant is associated with the following publications: (PMID: 26094658, 27713038, 28881617, 27498913, 32268276, Chan2021[article], 37803816, 33471991)
Genetic Services Laboratory, University of Chicago	RCV001816906	SCV002065731	uncertain significance	not specified	2021-10-15	criteria provided, single submitter	clinical testing	DNA sequence analysis of the FANCM gene demonstrated a sequence change, c.1597C>T, in exon 10 that results in an amino acid change, p.Arg533Cys. This sequence change has been described in the gnomAD database with a frequency of 0.056% in the non-Finnish European subpopulation (dbSNP rs146151355). The p.Arg533Cys change affects a highly conserved amino acid residue located in a domain of the FANCM protein that is known to be functional. The p.Arg533Cys substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). This sequence change has been previously described in an individual with breast cancer (PMID: 26094658). Due to insufficient evidences and the lack of functional studies, the clinical significance of the p.Arg533Cys change remains unknown at this time.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001574713	SCV002774591	uncertain significance	not provided	2023-01-25	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.001 (27/26122 chromosomes in Swedish subpopulation, http://gnomad.broadinstitute.org), is higher than would generally be expected for pathogenic variants in this gene. The variant has been reported in individuals with breast cancer (PMIDs: 26094658 (2015) and 33471991 (2021)) or other types of cancers including ovarian (PMIDs: 28881617 (2017) and 27713038 (2017)) as well as in unaffected controls (PMID: 33471991 (2021) and 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 damaging. Based on the available information, we are unable to determine the clinical significance of this variant.
Fulgent Genetics, Fulgent Genetics	RCV002487835	SCV002783916	uncertain significance	Spermatogenic failure 28; Premature ovarian failure 15	2022-04-26	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004538127	SCV004732095	uncertain significance	FANCM-related disorder	2023-10-26	no assertion criteria provided	clinical testing	The FANCM c.1597C>T variant is predicted to result in the amino acid substitution p.Arg533Cys. This variant was reported in an individual with breast cancer (Table S1, Aloraifi et al. 2015. PubMed ID: 26094658). This variant is reported in 0.056% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/14-45633577-C-T) and is interpreted as uncertain significance in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/663092/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.