ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.3539A>G (p.Lys1180Arg) (rs28897720)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000044217 SCV000072230 uncertain significance Hereditary breast and ovarian cancer syndrome 2019-12-23 criteria provided, single submitter clinical testing This sequence change replaces lysine with arginine at codon 1180 of the BRCA2 protein (p.Lys1180Arg). The lysine residue is moderately conserved and there is a small physicochemical difference between lysine and arginine. This variant is present in population databases (rs28897720, ExAC 0.003%). This variant has been reported in individuals affected with breast cancer in the Leiden Open-source Variation Database (PMID: 21520333). ClinVar contains an entry for this variant (Variation ID: 51484). 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 also 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. 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.
Ambry Genetics RCV000129986 SCV000184810 likely benign Hereditary cancer-predisposing syndrome 2018-02-14 criteria provided, single submitter clinical testing In silico models in agreement (benign);Other data supporting benign classification
GeneDx RCV000657117 SCV000279845 uncertain significance not provided 2018-05-16 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.3539A>G at the cDNA level, p.Lys1180Arg (K1180R) 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 3767A>G. This variant was observed in at least one woman reported to be at high risk for developing breast cancer based on personal and/or family history (Klemp 2000). BRCA2 Lys1180Arg 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 that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether BRCA2 Lys1180Arg is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Counsyl RCV000077307 SCV000488372 uncertain significance Breast-ovarian cancer, familial 2 2016-03-10 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000219144 SCV000602884 uncertain significance not specified 2017-03-23 criteria provided, single submitter clinical testing
Color RCV000129986 SCV000911105 benign Hereditary cancer-predisposing syndrome 2016-07-27 criteria provided, single submitter clinical testing
Mendelics RCV000077307 SCV001139066 uncertain significance Breast-ovarian cancer, familial 2 2019-05-28 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000219144 SCV001360640 uncertain significance not specified 2019-08-02 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.3539A>G (p.Lys1180Arg) results in a conservative amino acid change in 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 2.4e-05 in 250926 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.3539A>G has been reported in the literature in one individual affected with breast cancer (Klemp_2000) and one unaffected individual with a family history of pancreatic cancer (Abe_2019). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar (after 2014) with conflicting classifications (4X uncertain significance, 2x benign/ likely benign). Based on the evidence outlined above, the variant was classified as uncertain significance.
Sharing Clinical Reports Project (SCRP) RCV000077307 SCV000109104 uncertain significance Breast-ovarian cancer, familial 2 2011-08-19 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000077307 SCV000146254 uncertain significance Breast-ovarian cancer, familial 2 2004-02-20 no assertion criteria provided clinical testing

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