ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.6024G>C (p.Lys2008Asn) (rs56324666)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000129322 SCV000184085 uncertain significance Hereditary cancer-predisposing syndrome 2017-12-18 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
GeneDx RCV000590592 SCV000210379 uncertain significance not provided 2018-01-18 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.6024G>C at the cDNA level, p.Lys2008Asn (K2008N) at the protein level, and results in the change of a Lysine to an Asparagine (AAG>AAC). Using alternate nomenclature, this variant would be defined as BRCA2 6252G>C. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA2 Lys2008Asn was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the RAD51-binding domain (Roy 2012). In-silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether BRCA2 Lys2008Asn is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000204438 SCV000260122 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-07-23 criteria provided, single submitter clinical testing This sequence change replaces lysine with asparagine at codon 2008 of the BRCA2 protein (p.Lys2008Asn). The lysine residue is weakly conserved and there is a moderate physicochemical difference between lysine and asparagine. 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: 141008). 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 asparagine 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 RCV000409077 SCV000488258 uncertain significance Breast-ovarian cancer, familial 2 2016-02-09 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000160105 SCV000600675 uncertain significance not specified 2017-02-09 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000590592 SCV000694927 uncertain significance not provided 2017-07-26 criteria provided, single submitter clinical testing Variant summary: The BRCA2 c.6024G>C (p.Lys2008Asn) variant involves the alteration of a non-conserved nucleotide. 3/4 in silico tools predict a benign outcome for this variant (SNPsandGO not captured due to low reliability index). This variant is absent in 120460 control chromosomes. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. The variant of interest has not, to our knowledge, been reported in affected individuals via publications nor evaluated for functional impact by in vivo/vitro studies. Because of the absence of clinical information and the lack of functional studies, the variant is classified as a variant of uncertain significance (VUS) until additional information becomes available.
Mendelics RCV000204438 SCV000838828 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-07-02 criteria provided, single submitter clinical testing
Color RCV000129322 SCV000906124 uncertain significance Hereditary cancer-predisposing syndrome 2018-06-12 criteria provided, single submitter clinical testing

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