ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.83T>C (p.Leu28Pro) (rs80357266)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000588761 SCV000568438 uncertain significance not provided 2016-06-21 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.83T>C at the cDNA level, p.Leu28Pro (L28P) at the protein level, and results in the change of a Leucine to a Proline (CTG>CCG). Using alternate nomenclature, this variant would be defined as BRCA1 202T>C. This variant was observed in at least one individual with a personal and/or family history suspicious for Hereditary Breast and Ovarian Cancer (Kurian 2008). BRCA1 Leu28Pro was evaluated by yeast two-hybrid assay to have intact BARD1 and E3 binding, but reduced E3 ligase activity (Morris 2006). BRCA1 Leu28Pro 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 Leucine and Proline differ in some properties, this is considered a semi-conservative amino acid substitution. BRCA1 Leu28Pro occurs at a position that is conserved in mammals and is located in the ring figure domain and a region known to interact with multiple other proteins (Paul 2014). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, it is unclear whether BRCA1 Leu28Pro is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000588761 SCV000699317 uncertain significance not provided 2016-05-18 criteria provided, single submitter clinical testing Variant summary: The BRCA1 c.83T>C (p.Leu28Pro) variant involves the alteration of a conserved nucleotide and results in a replacement of an evolutionally conserved Leucine with a Proline. Residues 23-76 form the central RING motif and are thought to be critical zinc ion binding and E3 activity of BRCA1 (Brzovic_Nat Struct Biol_2001). Consistently, 4/5 in silico tools predict the variant to be deleterious. Furthermore, the variant is absent in 111144 control chromosomes and to our knowledge, it was not reported in affected patients with strong evidence for pathogenicity either at the time of this classification. Functional studies demonstrated the variant to be proficient in BARD1 binding, to slightly decrease UbcH5a binding and to reduce E3 ligase activity of BRCA1. Most importantly, Starita_Genetics_2015 reported the variant to negatively impact BRCA1s function in homology directed repair; a function known to be essential for tumor suppression, indicating a disease causing nature. Taken together, this variant is classified as variant of uncertain significance-possibly pathogenic until more information becomes available.
Color RCV000775198 SCV000909424 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-31 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000077631 SCV000109434 uncertain significance Breast-ovarian cancer, familial 1 2012-10-18 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000077631 SCV000144243 uncertain significance Breast-ovarian cancer, familial 1 2002-06-20 no assertion criteria provided clinical testing

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