ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.9011A>G (p.Lys3004Arg) (rs587782779)

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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 RCV000132316 SCV000187402 uncertain significance Hereditary cancer-predisposing syndrome 2018-03-18 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Color RCV000132316 SCV000689167 uncertain significance Hereditary cancer-predisposing syndrome 2018-05-07 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000160162 SCV000592247 uncertain significance not specified 2014-10-23 criteria provided, single submitter clinical testing
GeneDx RCV000656810 SCV000210491 uncertain significance not provided 2018-05-17 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.9011A>G at the cDNA level, p.Lys3004Arg (K3004R) at the protein level, and results in the change of a Lysine to an Arginine (AAG>AGG). Using alternate nomenclature, this variant would be defined as BRCA2 9239A>G. This variant has not, to our knowledge, been published in the literature as a pathogenic or benign germline variant. BRCA2 Lys3004Arg was not observed in large population cohorts (Lek 2016). BRCA2 Lys3004Arg is located in the DNA binding domain (Yang 2002). In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether BRCA2 Lys3004Arg is pathogenic or benign. We consider it to be a variant of uncertain significance.
GenomeConnect, ClinGen RCV000656810 SCV000986773 not provided not provided no assertion provided phenotyping only Variant interpretted as Uncertain significance and reported on 04/25/2018 by GTR ID Credit Valley Hospital Department of Laboratory Medicine. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.
Invitae RCV000530210 SCV000635710 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-11-16 criteria provided, single submitter clinical testing This sequence change replaces lysine with arginine at codon 3004 of the BRCA2 protein (p.Lys3004Arg). The lysine residue is weakly conserved and there is a small physicochemical difference between lysine and arginine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with a BRCA2-related disease. ClinVar contains an entry for this variant (Variation ID: 142866). 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 arginine 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, this variant has uncertain impact on BRCA2 function. The available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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