ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.3245A>G (p.Lys1082Arg) (rs80358569)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000587691 SCV000210311 uncertain significance not provided 2016-08-03 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.3245A>G at the cDNA level, p.Lys1082Arg (K1082R) at the protein level, and results in the change of a Lysine to an Arginine (AAA>AGA). Using alternate nomenclature, this variant would be defined as BRCA2 3473A>G. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA2 Lys1082Arg was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Lysine and Arginine share similar properties, this is considered a conservative amino acid substitution. BRCA2 Lys1082Arg occurs at a position that is not conserved and is located in the RAD51 binding domain (Roy 2012). In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available evidence, it is unclear whether BRCA2 Lys1082Arg is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000113150 SCV000296508 uncertain significance Breast-ovarian cancer, familial 2 2016-05-21 criteria provided, single submitter clinical testing
Ambry Genetics RCV000569193 SCV000666049 uncertain significance Hereditary cancer-predisposing syndrome 2017-08-24 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Integrated Genetics/Laboratory Corporation of America RCV000587691 SCV000694682 uncertain significance not provided 2017-01-13 criteria provided, single submitter clinical testing Variant summary: The BRCA2 c.3245A>G (p.Lys1082Arg) variant causes a missense change involving a non-conserved nucleotide, which 4/4 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 1/118788, which does not exceed the estimated maximal expected allele frequency for a pathogenic BRCA2 variant of 1/1333. The variant of interest has not been, to our knowledge, reported in affected individuals via publications. However, multiple clinical diagnostic/databases have cited the variant with a classification of "uncertain significance," along with BIC reported the variant to co-occur in an individual that carries a pathogenic BRCA1 variant, c.3331_3334delCAAG (p.Gln1111fsX5 - scored pathogenic). Therefore, until additional information becomes available, the variant of interest has been classified as a "Variant of Uncertain Significance (VUS)."
Counsyl RCV000113150 SCV000786494 uncertain significance Breast-ovarian cancer, familial 2 2018-05-14 criteria provided, single submitter clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000113150 SCV000146195 uncertain significance Breast-ovarian cancer, familial 2 2002-05-29 no assertion criteria provided clinical testing

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