ClinVar Miner

Submissions for variant NM_020937.4(FANCM):c.5108A>G (p.His1703Arg)

gnomAD frequency: 0.00021  dbSNP: rs146897650
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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 RCV000367982 SCV000751855 likely benign Fanconi anemia 2025-01-17 criteria provided, single submitter clinical testing
CeGaT Center for Human Genetics Tuebingen RCV000658691 SCV000780477 uncertain significance not provided 2017-12-01 criteria provided, single submitter clinical testing
GeneDx RCV000658691 SCV001822648 uncertain significance not provided 2024-11-18 criteria provided, single submitter clinical testing In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with personal or family history of breast or ovarian cancer, but also in unaffected controls (PMID: 36315097, 28881617, 22347400, 33471991); This variant is associated with the following publications: (PMID: 28881617, 22347400, 36315097, 33471991)
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000658691 SCV004218816 likely benign not provided 2023-01-16 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System RCV000658691 SCV001553974 uncertain significance not provided no assertion criteria provided clinical testing The FANCM p.His1703Arg variant was not identified in the literature nor was it identified in Cosmic. The variant was identified in dbSNP (ID: rs146897650), LOVD 3.0 and in ClinVar (classified as a VUS for Fanconi Anemia by Illumina, Invitae and Praxis fuer Humangenetik Tuebingen). The variant was identified in control databases in 85 of 282664 chromosomes at a frequency of 0.000301 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Ashkenazi Jewish in 67 of 10364 chromosomes (freq: 0.006465), Other in 4 of 7218 chromosomes (freq: 0.000554) and European (non-Finnish) in 14 of 128998 chromosomes (freq: 0.000109); it was not observed in the African, Latino, East Asian, European (Finnish), and South Asian populations. The p.His1703 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, and 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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