ClinVar Miner

Submissions for variant NM_000059.4(BRCA2):c.5005T>A (p.Leu1669Ile)

dbSNP: rs771336341
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000219696 SCV000279808 uncertain significance not provided 2016-01-20 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.5005T>A at the cDNA level, p.Leu1669Ile (L1669I) at the protein level, and results in the change of a Leucine to an Isoleucine (TTA>ATA). Using alternate nomenclature, this variant would be defined as BRCA2 5233T>A. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA2 Leu1669Ile 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 Isoleucine share similar properties, this is considered a conservative amino acid substitution. BRCA2 Leu1669Ile occurs at a position that is not conserved and is located in the 5th BRC repeat domain (Roy 2012). In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available evidence, it is unclear whether BRCA2 Leu1669Ile is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
University of Washington Department of Laboratory Medicine, University of Washington RCV003157468 SCV003852274 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).
Ambry Genetics RCV003157468 SCV004052570 uncertain significance Hereditary cancer-predisposing syndrome 2023-07-26 criteria provided, single submitter clinical testing The p.L1669I variant (also known as c.5005T>A), located in coding exon 10 of the BRCA2 gene, results from a T to A substitution at nucleotide position 5005. The leucine at codon 1669 is replaced by isoleucine, an amino acid with highly similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

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