ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.7781A>G (p.Lys2594Arg) (rs876660874)

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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 RCV000220613 SCV000278652 uncertain significance Hereditary cancer-predisposing syndrome 2016-09-12 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Color RCV000220613 SCV000911623 uncertain significance Hereditary cancer-predisposing syndrome 2018-05-16 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000765138 SCV000896364 uncertain significance Familial cancer of breast; Breast-ovarian cancer, familial 2; Fanconi anemia, complementation group D1; Medulloblastoma; Wilms tumor 1; Malignant tumor of prostate; Pancreatic cancer 2; Glioma susceptibility 3 2018-10-31 criteria provided, single submitter clinical testing
GeneDx RCV000479011 SCV000566271 uncertain significance not provided 2018-10-03 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.7781A>G at the cDNA level, p.Lys2594Arg (K2594R) 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 8009A>G. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA2 Lys2594Arg was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located within 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 information, it is unclear whether BRCA2 Lys2594Arg is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae RCV000637678 SCV000759148 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-05-22 criteria provided, single submitter clinical testing This sequence change replaces lysine with arginine at codon 2594 of the BRCA2 protein (p.Lys2594Arg). The lysine residue is moderately 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 BRCA2-related disease. ClinVar contains an entry for this variant (Variation ID: 234138). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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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