ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.9247A>G (p.Lys3083Glu) (rs80359190)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000221707 SCV000273391 uncertain significance Hereditary cancer-predisposing syndrome 2015-01-14 criteria provided, single submitter clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000031806 SCV000147577 uncertain significance Breast-ovarian cancer, familial 2 2001-02-16 no assertion criteria provided clinical testing
Color RCV000221707 SCV000689182 uncertain significance Hereditary cancer-predisposing syndrome 2018-10-01 criteria provided, single submitter clinical testing
GeneDx RCV000590395 SCV000210498 uncertain significance not provided 2018-07-06 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.9247A>G at the cDNA level, p.Lys3083Glu (K3083E) at the protein level, and results in the change of a Lysine to a Glutamic Acid (AAA>GAA). This variant, also denoted BRCA2 9475A>G using alternate nomenclature, has been observed in at least one individual with a personal and family history of breast cancer (Miramar 2008). BRCA2 Lys3083Glu was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located within the DNA binding domain (Yang 2002). In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available information, it is unclear whether BRCA2 Lys3083Glu is pathogenic or benign. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000590395 SCV000695222 uncertain significance not provided 2017-06-29 criteria provided, single submitter clinical testing Variant summary: The BRCA2 c.9247A>G (p.Lys3083Glu) variant involves the alteration of a conserved nucleotide, resulting in a missense change in the nucleic acid-binding, OB-fold (InterPro). 3/4 in silico tools predict a damaging outcome for this variant ( SNPsandGO not accessible at the time of evaluation). This variant was found in the large control database ExAC at a frequency of 0.0000166 (2/120418 control chromosomes), which does not exceed the estimated maximal expected allele frequency of a pathogenic BRCA2 variant (0.0007503). The variant has been identified in one patient with breast or ovarian cancer without strong evidence for pathogenicity (Miramar_2008) and computational likelihood estimates suggest the variant is neutral (Karchin_2008). However, the function of the variant has not been tested via in vitro/vivo studies. In addition, multiple clinical diagnostic laboratories/reputable databases have classified this variant as uncertain significance. Taken together, this variant is classified as VUS until additional information becomes available.
Invitae RCV000045756 SCV000073769 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-10-01 criteria provided, single submitter clinical testing This sequence change replaces lysine with glutamic acid at codon 3083 of the BRCA2 protein (p.Lys3083Glu). The lysine residue is moderately conserved and there is a small physicochemical difference between lysine and glutamic acid. This variant is present in population databases (rs80359190, ExAC 0.003%). This variant has been reported in an individual affected with breast cancer (PMID: 18176857). ClinVar contains an entry for this variant (Variation ID: 38223). An algorithm developed specifically for the BRCA2 gene suggests that this missense change is likely to be tolerated (PMID: 19043619). However, this prediction has not been confirmed by published functional studies and its 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.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000590395 SCV000889178 uncertain significance not provided 2018-01-05 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000031806 SCV000054414 uncertain significance Breast-ovarian cancer, familial 2 2012-04-24 no assertion criteria provided clinical testing

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