Submissions for variant NM_020937.4(FANCM):c.5832G>T (p.Leu1944Phe)

gnomAD frequency: 0.00012  dbSNP: rs201017015

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000809180	SCV000949322	uncertain significance	Fanconi anemia	2023-10-05	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 1944 of the FANCM protein (p.Leu1944Phe). This variant is present in population databases (rs201017015, gnomAD 0.05%). 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: 653408). 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	RCV001664428	SCV001875344	uncertain significance	not provided	2024-07-29	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 ovarian or breast cancer, but also in unaffected controls (PMID: 26689913, 28881617, 33471991); This variant is associated with the following publications: (PMID: 28881617, 26689913, 33471991)
Genetic Services Laboratory, University of Chicago	RCV001816879	SCV002070090	uncertain significance	not specified	2020-01-13	criteria provided, single submitter	clinical testing	DNA sequence analysis of the FANCM gene demonstrated a sequence change, c.5832G>T, in exon 22 that results in an amino acid change, p.Leu1944Phe. 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 frequency of 0.06% in Ashkenazi Jewish populations (dbSNP rs201017015). The p.Leu1944Phe change affects a moderately conserved amino acid residue located in a domain of the FANCM protein that is known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Leu1944Phe substitution. Due to the lack of functional studies, the clinical significance of the p.Leu1944Phe change remains unknown at this time.
Sema4, Sema4	RCV002259022	SCV002529888	uncertain significance	Hereditary cancer-predisposing syndrome	2021-09-30	criteria provided, single submitter	curation
Fulgent Genetics, Fulgent Genetics	RCV002495113	SCV002804085	uncertain significance	Spermatogenic failure 28; Premature ovarian failure 15	2022-01-05	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001664428	SCV004218831	uncertain significance	not provided	2023-06-10	criteria provided, single submitter	clinical testing	In the published literature, this variant has been reported in an unaffected control in a study of high grade serous ovarian cancer cases (PMID: 28881617 (2017)). Additionally, it has also been reported in individuals with breast cancer as well as in unaffected controls (PMIDs: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/FANCM)). The frequency of this variant in the general population, 0.00058 (6/10366 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.
Mendelics	RCV003492175	SCV004232592	likely benign	Hereditary cancer	2024-01-23	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV001664428	SCV004810981	uncertain significance	not provided	2024-03-01	criteria provided, single submitter	clinical testing