ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.5683G>A (p.Glu1895Lys) (rs146351301)

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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 RCV000131358 SCV000186334 likely benign Hereditary cancer-predisposing syndrome 2018-07-24 criteria provided, single submitter clinical testing In silico models in agreement (benign);Other strong data supporting benign classification
Laboratory of Molecular Diagnosis of Cancer,West China Hospital, Sichuan University RCV000240768 SCV000265934 uncertain significance Neoplasm of the breast 2015-11-01 criteria provided, single submitter research
Invitae RCV000227239 SCV000283268 uncertain significance Hereditary breast and ovarian cancer syndrome 2019-08-31 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with lysine at codon 1895 of the BRCA2 protein (p.Glu1895Lys). The glutamic acid residue is weakly conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is present in population databases (rs146351301, ExAC 0.009%). This variant has been reported in individuals affected with breast cancer (PMID: 25682074, 20104584, 27257965, 28664449, Invitae). However, in one of these individuals a pathogenic allele was also identified in BRCA2, which suggests that this c.5683G>A variant was not the primary cause of disease. In the literature, this variant is also known as 5911G>A. ClinVar contains an entry for this variant (Variation ID: 142307). 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 lysine 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, 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.
GeneDx RCV000590426 SCV000567968 uncertain significance not provided 2018-02-19 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.5683G>A at the cDNA level, p.Glu1895Lys (E1895K) at the protein level, and results in the change of a Glutamic Acid to a Lysine (GAG>AAG). Using alternate nomenclature, this variant would be defined as BRCA2 5911G>A. This variant was observed in at least four individuals with breast cancer (Borg 2010, Wong-Brown 2015, Zhong 2016, Li 2017), and in at least two healthy Japanese individuals undergoing whole genome sequencing (Yamaguchi-Kabata 2018). BRCA2 Glu1895Lys was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located within 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 Glu1895Lys is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000486300 SCV000591988 uncertain significance not specified 2016-03-21 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000590426 SCV000694890 uncertain significance not provided 2016-05-09 criteria provided, single submitter clinical testing Variant summary: The BRCA2 c.5683G>A (p.Glu1895Lys) variant involves the alteration of a non-conserved nucleotide. 4/5 in silico tools predict a benign outcome. This variant was found in 1/120622 control chromosomes at a frequency of 0.0000083, which does not exceed the estimated maximal expected allele frequency of a pathogenic BRCA2 variant (0.0007503). The variant was reported in affected individuals in the literature, without strong evidence for causality. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as VUS. Because of the absence of clinical information and the lack of functional studies, the variant was classified as a variant of uncertain significance (VUS) until additional information becomes available.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000590426 SCV000889073 uncertain significance not provided 2017-11-24 criteria provided, single submitter clinical testing
Color RCV000131358 SCV000903231 likely benign Hereditary cancer-predisposing syndrome 2015-10-21 criteria provided, single submitter clinical testing
Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics RCV000999647 SCV001135002 uncertain significance Breast-ovarian cancer, familial 2 2019-10-24 criteria provided, single submitter clinical testing A heterozygous missense variation in exon 11 of the BRCA2 gene that results in the amino acid substitution of Lysine for Glutamic Acid at codon 1895 was detected. The observed variation has previously been reported in patients affected with breast cancer (Borg et al 2010, Zhong et al 2016, Li et al 2017). The observed variant c.5683G>A (p.Glu1895Lys) has a minor allele frequency of 0.02% and 0.001% in the 1000 Genomes and ExAC databases respectively. The reference codon is conserved across primates. In summary, the variant meets our criteria to be classified as variant of unknown significance.

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