ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.5487G>T (p.Leu1829Phe) (rs779967765)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000574898 SCV000673106 uncertain significance Hereditary cancer-predisposing syndrome 2016-10-31 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Color RCV000574898 SCV000683707 uncertain significance Hereditary cancer-predisposing syndrome 2018-06-15 criteria provided, single submitter clinical testing
GeneDx RCV000482177 SCV000565920 uncertain significance not provided 2015-03-10 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.5487G>T at the cDNA level, p.Leu1829Phe (L1829F) at the protein level, and results in the change of a Leucine to a Phenylalanine (TTG>TTT). Using alternate nomenclature, this variant would be defined as BRCA2 5715G>T. This variant has not, to our knowledge, been published in the literature as either a germline pathogenic variant or a benign polymorphism. However, this variant has been reported as a somatic variant in a breast tumor (Harismendy 2013). BRCA2 Leu1829Phe was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Leucine and Phenylalanine share similar properties, this is considered a conservative amino acid substitution. BRCA2 Leu1829Phe occurs at a position that is not conserved across species and is not located in a known functional domain (UniProt). In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available information, it is unclear whether BRCA2 Leu1829Phe is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae RCV000456588 SCV000549585 uncertain significance Hereditary breast and ovarian cancer syndrome 2016-12-06 criteria provided, single submitter clinical testing This sequence change replaces leucine with phenylalanine at codon 1829 of the BRCA2 protein (p.Leu1829Phe). The leucine residue is weakly conserved and there is a small physicochemical difference between leucine and phenylalanine. This variant is present in population databases (rs779967765, ExAC 0.01%). This variant has been reported in an individual affected with breast cancer (PMID: 27257965). ClinVar contains an entry for this variant (Variation ID: 224465). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: (SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). The phenylalanine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies. In summary, this variant is a rare missense change that is not predicted to affect protein function. It has been reported in both the population and affected individuals, but the available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Laboratory of Molecular Diagnosis of Cancer,West China Hospital, Sichuan University RCV000240748 SCV000265945 uncertain significance Neoplasm of the breast 2015-11-01 criteria provided, single submitter research

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