ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.4068G>T (p.Leu1356Phe) (rs28897724)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000129289 SCV000184050 uncertain significance Hereditary cancer-predisposing syndrome 2017-02-27 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Color RCV000129289 SCV000906074 uncertain significance Hereditary cancer-predisposing syndrome 2018-09-26 criteria provided, single submitter clinical testing
GeneDx RCV000483121 SCV000570615 uncertain significance not provided 2016-06-08 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.4068G>T at the cDNA level, p.Leu1356Phe (L1356F) 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 4296G>T. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA2 Leu1356Phe 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 Phenylalanine share similar properties, this is considered a conservative amino acid substitution. BRCA2 Leu1356Phe occurs at a position that is not conserved and is located in the RAD51 and POLH binding domains (Roy 2012, Buisson 2014). 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 Leu1356Phe is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000227395 SCV000283226 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-09-03 criteria provided, single submitter clinical testing This sequence change replaces leucine with phenylalanine at codon 1356 of the BRCA2 protein (p.Leu1356Phe). The leucine residue is moderately conserved and there is a small physicochemical difference between leucine and phenylalanine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with BRCA2-related disease. ClinVar contains an entry for this variant (Variation ID: 140989). 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 and their clinical significance is uncertain. 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.

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