ClinVar Miner

Submissions for variant NM_000059.4(BRCA2):c.3073A>G (p.Lys1025Glu) (rs80358550)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001083912 SCV000072125 likely benign Hereditary breast and ovarian cancer syndrome 2020-11-17 criteria provided, single submitter clinical testing
Ambry Genetics RCV000131460 SCV000186444 likely benign Hereditary cancer-predisposing syndrome 2018-05-08 criteria provided, single submitter clinical testing In silico models in agreement (benign);Other data supporting benign classification
GeneDx RCV000044112 SCV000210586 likely benign not specified 2017-07-21 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Department of Pathology and Molecular Medicine,Queen's University RCV000044112 SCV000588088 uncertain significance not specified 2017-04-20 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000586348 SCV000694664 likely benign not provided 2017-01-18 criteria provided, single submitter clinical testing Variant summary: The BRCA2 c.3073A>G (p.Lys1025Glu) variant located in the BRCA2 repeat domain that causes a missense change involving a conserved nucleotide, which 3/4 in silico tools (SNPs&GO not captured due to low reliability index) predict a benign outcome., although these predictions have yet to be functionally assessed. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 5/120308 (1/24038), which does not exceed the estimated maximal expected allele frequency for a pathogenic BRCA2 variant of 1/1333. Multiple publications have cited the variant in affected individuals, in particular, one study, Yacoub_2007, cites the variant to occur in a man diagnosed with prostate cancer, who's daughter was diagnosed with breast cancer but did not carry the variant of interest, therefore, indicating the variant does not segregate with disease. An internal LCA sample reports the variant to co-occur with a pathogenic BRCA1 variant, c.1360_1361delAG. In addition, multiple clinical diagnostic laboratories/databases cite the variant with a classification from "uncertain significance" to "likely benign/benign." Therefore, the variant of interest was classified as "likely benign."
PreventionGenetics,PreventionGenetics RCV000586348 SCV000805684 uncertain significance not provided 2018-01-10 criteria provided, single submitter clinical testing
Color Health, Inc RCV000131460 SCV000910901 benign Hereditary cancer-predisposing syndrome 2016-04-05 criteria provided, single submitter clinical testing
Mayo Clinic Laboratories, Mayo Clinic RCV000586348 SCV001716148 uncertain significance not provided 2019-11-14 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000077290 SCV000109087 benign Breast-ovarian cancer, familial 2 2012-03-02 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000077290 SCV000146164 uncertain significance Breast-ovarian cancer, familial 2 2004-02-20 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001354029 SCV000591847 uncertain significance Malignant tumor of breast no assertion criteria provided clinical testing The p.Lys1025Glu variant has been reported as a variant of unknown significance in the BIC (x5) and UMD (x2) databases. It has also been reported once in the literaure in a case report of male breast cancer in a patient receiving leuprolide therapy for prostate cancer (Yacoub_2007_17679929). It has not been previously identified by our laboratory. In addition, the variant is listed in the dbSNP database (ID#:rs80358550) as coming from a "clinical source" but no frequency information was provided, and so the prevalence of this variant in the population is not known. This residue is not conserved in mammals and computational analyses (PolyPhen2, SIFT, AlignGVGD) do not suggest a high likelihood of impact to the protein. However, this information is not predictive enough to rule out pathogenicity. In summary, based on the above information, the clinical significance of this variant cannot be determined at this time. This variant is classified as a variant of unknown significance.

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