ClinVar Miner

Submissions for variant NM_000135.4(FANCA):c.3795G>T (p.Leu1265Phe)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
St. Jude Molecular Pathology, St. Jude Children's Research Hospital RCV002292227 SCV002584638 uncertain significance Fanconi anemia complementation group A 2022-09-20 criteria provided, single submitter clinical testing The FANCA c.3795G>T (p.Leu1265Phe) missense change is absent in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL predicts a deleterious effect on protein function, but to our knowledge this prediction has not been confirmed by functional studies. This variant has been reported as heterozygous in at least one individual with head and neck squamous cell carcinoma (PMID: 2867840). To our knowledge, this variant has not been reported in individuals with Fanconi anemia. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp RCV003523126 SCV004363929 uncertain significance Fanconi anemia 2023-03-07 criteria provided, single submitter clinical testing This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 1265 of the FANCA protein (p.Leu1265Phe). 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. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt FANCA protein function. ClinVar contains an entry for this variant (Variation ID: 1710940). This missense change has been observed in individual(s) with head and neck squamous cell carcinoma (PMID: 28678401). This variant is not present in population databases (gnomAD no frequency).

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