Submissions for variant NM_020937.4(FANCM):c.2996C>T (p.Pro999Leu)

gnomAD frequency: 0.00044  dbSNP: rs148304968

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000698336	SCV000826996	uncertain significance	Fanconi anemia	2024-01-30	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 999 of the FANCM protein (p.Pro999Leu). This variant is present in population databases (rs148304968, gnomAD 0.1%). This missense change has been observed in individual(s) with colorectal cancer (PMID: 31428572). ClinVar contains an entry for this variant (Variation ID: 575971). 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.
Cancer Genomics Group, Japanese Foundation For Cancer Research	RCV001030481	SCV001193589	uncertain significance	Hereditary breast ovarian cancer syndrome	2019-05-01	criteria provided, single submitter	research
GeneDx	RCV001662769	SCV001874071	uncertain significance	not provided	2023-01-25	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in an individual with head and neck squamous cell carcinoma (Lu et al., 2015); This variant is associated with the following publications: (PMID: 26689913)
Genetic Services Laboratory, University of Chicago	RCV001816721	SCV002065682	uncertain significance	not specified	2021-08-24	criteria provided, single submitter	clinical testing	DNA sequence analysis of the FANCM gene demonstrated a sequence change, c.2996C>T, in exon 14 that results in an amino acid change, p.Pro999Leu. This sequence change has been described in the gnomAD database with a frequency of 0.15% in the African/African-American subpopulation (dbSNP rs148304968). The p.Pro999Leu change affects a highly 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.Pro999Leu substitution. This sequence change does not appear to have been previously described in individuals with FANCM-related disorders. Due to insufficient evidences and the lack of functional studies, the clinical significance of the p.Pro999Leu change remains unknown at this time.
Sema4, Sema4	RCV002256479	SCV002527344	uncertain significance	Hereditary cancer-predisposing syndrome	2021-08-19	criteria provided, single submitter	curation
Fulgent Genetics, Fulgent Genetics	RCV002477590	SCV002787365	uncertain significance	Spermatogenic failure 28; Premature ovarian failure 15	2022-03-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV003243265	SCV003940644	uncertain significance	Inborn genetic diseases	2023-04-27	criteria provided, single submitter	clinical testing	The c.2996C>T (p.P999L) alteration is located in coding exon 14 of the FANCM gene. This alteration results from a C to T substitution at nucleotide position 2996, causing the proline (P) at amino acid position 999 to be replaced by a leucine (L). Based on data from gnomAD, the T allele has an overall frequency of 0.029% (81/281220) total alleles studied. The highest observed frequency was 0.146% (36/24630) of African alleles. This amino acid position is highly conserved in available vertebrate species. This alteration is predicted to be tolerated by in silico analysis. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Neuberg Supratech Reference Laboratories Pvt Ltd, Neuberg Centre for Genomic Medicine	RCV003446359	SCV004171923	uncertain significance	Premature ovarian failure 15		criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001662769	SCV004218755	uncertain significance	not provided	2023-06-04	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.0015 (36/24630 chromosomes in African/African American subpopulation, http://gnomad.broadinstitute.org), is higher than would generally be expected for pathogenic variants in this gene. In the published literature, the variant has been reported in individuals affected with rectal cancer (PMID: 31428572 (2019)) and myelodysplastic syndrome (PMID: 36534659 (2022)). 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.