ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.5893C>T (p.Leu1965Phe) (rs398122542)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000215394 SCV000274563 likely benign Hereditary cancer-predisposing syndrome 2015-12-08 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000657041 SCV000296533 uncertain significance not provided 2019-05-07 criteria provided, single submitter clinical testing
GeneDx RCV000657041 SCV000567176 uncertain significance not provided 2017-08-23 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.5893C>T at the cDNA level, p.Leu1965Phe (L1965F) at the protein level, and results in the change of a Leucine to a Phenylalanine (CTT>TTT). Using alternate nomenclature, this variant would be defined as BRCA2 6121C>T. This variant has been identified in at least one individual with a personal history of early-onset breast cancer (Lee 2008). BRCA2 Leu1965Phe was not observed at a significant allele frequency in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Leucine and Phenylalanine share similar properties, this is considered a conservative amino acid substitution. BRCA2 Leu1965Phe occurs at a position that is not conserved and is located in RAD51 interaction domain (Roy 2012). 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 Leu1965Phe is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000637433 SCV000758892 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-10-29 criteria provided, single submitter clinical testing This sequence change replaces leucine with phenylalanine at codon 1965 of the BRCA2 protein (p.Leu1965Phe). The leucine residue is weakly conserved and there is a small physicochemical difference between leucine and phenylalanine. This variant is present in population databases (rs398122542, ExAC 0.02%). This variant has been reported in an individual affected with breast cancer (PMID: 18284688). ClinVar contains an entry for this variant (Variation ID: 91427). 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.
Counsyl RCV000076944 SCV000784947 uncertain significance Breast-ovarian cancer, familial 2 2017-02-10 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000076944 SCV000108741 uncertain significance Breast-ovarian cancer, familial 2 2012-04-18 no assertion criteria provided clinical testing

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