ClinVar Miner

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

gnomAD frequency: 0.00027  dbSNP: rs200360968
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Total submissions: 7
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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.

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