ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.62A>G (p.Lys21Arg) (rs397507367)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000122923 SCV000166181 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-11-12 criteria provided, single submitter clinical testing This sequence change replaces lysine with arginine at codon 21 of the BRCA2 protein (p.Lys21Arg). The lysine residue is weakly conserved and there is a small physicochemical difference between lysine and arginine. This variant is present in population databases (rs397507367, ExAC 0.03%). This variant has been reported in individuals affected with breast cancer (PMID: 25503501, 29409476). ClinVar contains an entry for this variant (Variation ID: 38033). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but 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.
Ambry Genetics RCV000129552 SCV000184332 uncertain significance Hereditary cancer-predisposing syndrome 2017-04-12 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Rarity in general population databases (dbsnp, esp, 1000 genomes),Insufficient or conflicting evidence,In silico models in agreement (benign)
GeneDx RCV000656792 SCV000210251 uncertain significance not provided 2018-05-17 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.62A>G at the cDNA level, p.Lys21Arg (K21R) 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 290A>G. This variant was observed in at least two individuals with early onset breast cancer (Maxwell 2014, Abdel-Razeq 2018). BRCA2 Lys21Arg was not observed at a significant allele frequency in large population cohorts (Lek 2016). Since Lysine and Arginine share similar properties, this is considered a conservative amino acid substitution. BRCA2 Lys21Arg is located within the region of interaction with PALB2 (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 Lys21Arg is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Counsyl RCV000031614 SCV000487822 uncertain significance Breast-ovarian cancer, familial 2 2015-11-21 criteria provided, single submitter clinical testing
Color RCV000129552 SCV000537556 uncertain significance Hereditary cancer-predisposing syndrome 2018-09-12 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000656792 SCV000600690 uncertain significance not provided 2019-07-19 criteria provided, single submitter clinical testing
Mendelics RCV000122923 SCV000838718 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-07-02 criteria provided, single submitter clinical testing
Mendelics RCV000031614 SCV001138937 uncertain significance Breast-ovarian cancer, familial 2 2019-05-28 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000031614 SCV000054221 uncertain significance Breast-ovarian cancer, familial 2 2011-10-31 no assertion criteria provided clinical testing

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