ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.3106T>C (p.Phe1036Leu)

gnomAD frequency: 0.00001  dbSNP: rs766381694
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000254861 SCV000321426 uncertain significance not provided 2016-07-11 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.3106T>C at the cDNA level, p.Phe1036Leu (F1036L) at the protein level, and results in the change of a Phenylalanine to a Leucine (TTT>CTT). Using alternate nomenclature, this variant would be defined as BRCA1 3225T>C. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA1 Phe1036Leu was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Phenylalanine and Leucine share similar properties, this is considered a conservative amino acid substitution. BRCA1 Phe1036Leu occurs at a position that is not conserved and is located within the DNA binding domain and a region known to interact with RAD51 (Chen 1998, Narod 2004). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available information, it is unclear whether BRCA1 Phe1036Leu is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae RCV000551637 SCV000635883 uncertain significance Hereditary breast ovarian cancer syndrome 2022-09-04 criteria provided, single submitter clinical testing This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 1036 of the BRCA1 protein (p.Phe1036Leu). This variant is present in population databases (rs766381694, gnomAD 0.0009%). This variant has not been reported in the literature in individuals affected with BRCA1-related conditions. ClinVar contains an entry for this variant (Variation ID: 265049). 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 not expected to disrupt BRCA1 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.
University of Washington Department of Laboratory Medicine, University of Washington RCV003157502 SCV003849127 likely benign Hereditary cancer-predisposing syndrome 2023-03-23 criteria provided, single submitter curation Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673).

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