ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.9175A>G (p.Lys3059Glu) (rs80359174)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000130061 SCV000184888 likely benign Hereditary cancer-predisposing syndrome 2018-03-30 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Other data supporting benign classification,In silico models in agreement (benign)
Breast Cancer Information Core (BIC) (BRCA2) RCV000114059 SCV000147558 uncertain significance Breast-ovarian cancer, familial 2 2004-02-20 no assertion criteria provided clinical testing
Color RCV000130061 SCV000903036 likely benign Hereditary cancer-predisposing syndrome 2017-09-22 criteria provided, single submitter clinical testing
Counsyl RCV000114059 SCV000488180 uncertain significance Breast-ovarian cancer, familial 2 2016-01-19 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000217640 SCV000592262 uncertain significance not specified 2013-09-26 criteria provided, single submitter clinical testing
GeneDx RCV000766656 SCV000278886 uncertain significance not provided 2015-09-23 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.9175A>G at the cDNA level, p.Lys3059Glu (K3059E) at the protein level, and results in the change of a Lysine to a Glutamic Acid (AAA>GAA). Using alternate nomenclature, this variant would be defined as BRCA2 9403A>G. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA2 Lys3059Glu was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Lysine and Glutamic Acid differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA2 Lys3059Glu occurs at a position that is not conserved and is located in the DNA binding domain (Borg 2010, 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 Lys3059Glu is pathogenic or benign. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000217640 SCV000918983 uncertain significance not specified 2018-07-30 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.9175A>G (p.Lys3059Glu) results in a conservative amino acid change located in the BRCA2, OB3 domain of the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4.1e-06 in 246114 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.9175A>G in individuals affected with Hereditary Breast and Ovarian Cancer and no experimental evidence demonstrating its impact on protein function have been reported. Co-occurrence with a pathogenic variant has been reported (BRCA2 c.8237_8238delCA/p.Thr2746Serfs; BRCA2 c.8575delC/p.Q2859fsX4), providing supporting evidence for a benign role. Four ClinVar submissions from other clinical diagnostic laboratories (evaluation after 2014) cite the variant as uncertain significance (2x) and likely benign (2x). Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
Invitae RCV000045737 SCV000073750 likely benign Hereditary breast and ovarian cancer syndrome 2017-11-04 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000114059 SCV000297577 likely benign Breast-ovarian cancer, familial 2 2011-07-05 no assertion criteria provided clinical testing

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