ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.1534C>G (p.Leu512Val) (rs41286294)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000130372 SCV000185226 uncertain significance Hereditary cancer-predisposing syndrome 2017-02-23 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: In silico models in agreement (deleterious) and/or completely conserved position in appropriate species
Invitae RCV000198821 SCV000254957 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-10-11 criteria provided, single submitter clinical testing This sequence change replaces leucine with valine at codon 512 of the BRCA1 protein (p.Leu512Val). The leucine residue is highly conserved and there is a small physicochemical difference between leucine and valine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals affected with breast cancer (PMID: 26689913). ClinVar contains an entry for this variant (Variation ID: 141741). In a functional study of the impact of BRCA1 missense variants on DNA repair, this variant has been reported to have activity similar to that of wild-type BRCA1 (PMID: 26689913). 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.
GeneDx RCV000758787 SCV000566052 uncertain significance not provided 2016-03-30 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.1534C>G at the cDNA level, p.Leu512Val (L512V) at the protein level, and results in the change of a Leucine to a Valine (CTT>GTT). Using alternate nomenclature, this variant would be defined as BRCA1 1653C>G. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA1 Leu512Val 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 Valine share similar properties, this is considered a conservative amino acid substitution. BRCA1 Leu512Val occurs at a position that is conserved across species and is located in the DNA binding domain and a region known to interact with multiple other proteins (Narod 2004, Paul 2014). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether BRCA1 Leu512Val is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000483013 SCV000600255 uncertain significance not specified 2017-07-08 criteria provided, single submitter clinical testing
Color RCV000130372 SCV000682970 uncertain significance Hereditary cancer-predisposing syndrome 2018-06-16 criteria provided, single submitter clinical testing
Counsyl RCV000662675 SCV000785382 uncertain significance Breast-ovarian cancer, familial 1 2017-07-19 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000758787 SCV000887626 uncertain significance not provided 2018-01-15 criteria provided, single submitter clinical testing

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