Submissions for variant NM_020937.4(FANCM):c.4934G>A (p.Arg1645His)

gnomAD frequency: 0.00006  dbSNP: rs377502779

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000815706	SCV000956172	uncertain significance	Fanconi anemia	2024-01-23	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 1645 of the FANCM protein (p.Arg1645His). This variant is present in population databases (rs377502779, gnomAD 0.02%). This missense change has been observed in individual(s) with breast and/or ovarian cancer (PMID: 29351780). ClinVar contains an entry for this variant (Variation ID: 658816). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The histidine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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	RCV002307626	SCV002601275	uncertain significance	not provided	2023-05-08	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 and/or ovarian cancer (Nguyen-Dumont et al., 2018); This variant is associated with the following publications: (PMID: 29351780)
Fulgent Genetics, Fulgent Genetics	RCV002487794	SCV002787434	uncertain significance	Spermatogenic failure 28; Premature ovarian failure 15	2021-12-29	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV002307626	SCV003833941	uncertain significance	not provided	2019-11-19	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV002307626	SCV004218812	uncertain significance	not provided	2023-04-25	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.0002 (5/24908 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. The variant has been reported in individuals with breast and/or ovarian cancer as well as unaffected controls (PMIDs: 29351780 (2018) and 33471991 (2021), 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 benign. Based on the available information, we are unable to determine the clinical significance of this variant.
Mendelics	RCV004702449	SCV005205569	likely benign	Hereditary cancer	2024-09-11	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following: it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease, and/or has normal protein function, and/or has lack of segregation with disease, and/or has been detected in co-occurrence with known pathogenic variant, and/or has lack of disease association in case-control studies, and/or is located in a region inconsistent with a known cause of pathogenicity.