ClinVar Miner

Submissions for variant NM_020937.4(FANCM):c.4318-3T>G

gnomAD frequency: 0.00003  dbSNP: rs367696095
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000796235 SCV000935740 uncertain significance Fanconi anemia 2024-01-23 criteria provided, single submitter clinical testing This sequence change falls in intron 15 of the FANCM gene. It does not directly change the encoded amino acid sequence of the FANCM protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs367696095, gnomAD 0.01%). 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: 642722). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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.
Mendelics RCV002249509 SCV002517064 uncertain significance not specified 2022-05-04 criteria provided, single submitter clinical testing
Fulgent Genetics, Fulgent Genetics RCV002507375 SCV002803232 uncertain significance Spermatogenic failure 28; Premature ovarian failure 15 2021-11-19 criteria provided, single submitter clinical testing
GeneDx RCV003238812 SCV003936405 uncertain significance not provided 2023-06-30 criteria provided, single submitter clinical testing Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on splicing; Has not been previously published as pathogenic or benign to our knowledge
PreventionGenetics, part of Exact Sciences RCV004738010 SCV005344760 uncertain significance FANCM-related disorder 2024-08-28 no assertion criteria provided clinical testing The FANCM c.4318-3T>G variant is predicted to interfere with splicing. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.014% of alleles in individuals of Latino descent in gnomAD and is reported as a variant of uncertain signifiance in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/642722/). Of note, another variant impacting the c.4318-1G>A splice site has been reported in an individual with breast cancer, however that patient also had a RAD51D missense variant (Patient ID 144, Akbar et al. 2022. PubMed ID: 35710434 ). Although we suspect that the c.4318-3T>G variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

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