Submissions for variant NM_020937.4(FANCM):c.4366C>T (p.Arg1456Cys)

gnomAD frequency: 0.00027  dbSNP: rs200360968

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000378941	SCV000547798	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 1456 of the FANCM protein (p.Arg1456Cys). This variant is present in population databases (rs200360968, 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: 313218). 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 cysteine 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.
Fulgent Genetics, Fulgent Genetics	RCV000765163	SCV000896392	uncertain significance	Spermatogenic failure 28; Premature ovarian failure 15	2022-04-22	criteria provided, single submitter	clinical testing
GeneDx	RCV001357884	SCV001771338	uncertain significance	not provided	2023-07-20	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 other cancers and in unaffected controls (Broderick et al., 2017; Dicks et al., 2017); Observed in an individual with familial pulmonary fibrosis and shortened telomeres who also harbored variants in RTEL1 and RAD51C (Arias-Salgado et al., 2019); This variant is associated with the following publications: (PMID: 27713038, 29641532, 27525107, 30995915, 28881617)
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV001357884	SCV002011480	uncertain significance	not provided	2021-11-03	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV001357884	SCV004134051	likely benign	not provided	2023-12-01	criteria provided, single submitter	clinical testing	FANCM: BP4
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001357884	SCV004218801	likely benign	not provided	2023-05-17	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001357884	SCV001553479	uncertain significance	not provided		no assertion criteria provided	clinical testing	The FANCM p.Arg1430Cys variant was not identified in the literature nor was it identified in Cosmic. The variant was identified in dbSNP (ID: rs200360968), ClinVar (classified as a VUS by Illumina, Invitae and Fulgent Genetics) and LOVD 3.0. The variant was also identified in control databases in 69 of 275248 chromosomes at a frequency of 0.000251 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European (Non-Finnish) in 62 of 125766 chromosomes (freq: 0.000493), Other in 2 of 6406 chromosomes (freq: 0.000312), South Asian in 3 of 30664 chromosomes (freq: 0.000098) and Latino in 2 of 34284 chromosomes (freq: 0.000058), while the variant was not observed in the African, Ashkenazi Jewish, East Asian, and European (Finnish) populations. The p.Arg1430 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.