ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.4854T>A (p.Asp1618Glu) (rs80358708)

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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 RCV000222179 SCV000275810 uncertain significance Hereditary cancer-predisposing syndrome 2017-03-13 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Counsyl RCV000077339 SCV000489567 uncertain significance Breast-ovarian cancer, familial 2 2016-10-31 criteria provided, single submitter clinical testing
GeneDx RCV000590643 SCV000564783 uncertain significance not provided 2018-10-11 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.4854T>A at the cDNA level, p.Asp1618Glu (D1618E) at the protein level, and results in the change of an Aspartic Acid to a Glutamic Acid (GAT>GAA). Using alternate nomenclature, this variant would be defined as BRCA2 5082T>A. This variant has been observed in individuals with breast cancer, as well as individuals being evaluated for hereditary breast and ovarian cancer (Park 2016, Arai 2017, Park 2017). BRCA2 Asp1618Glu was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the RAD51 and POLH binding domains (Roy 2012, Buisson 2014). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether BRCA2 Asp1618Glu is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000479674 SCV000600613 uncertain significance not specified 2016-12-30 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000479674 SCV000694807 uncertain significance not specified 2019-07-22 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.4854T>A (p.Asp1618Glu) 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 249914 control chromosomes exclusively among individuals of East Asian ancestry. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.4854T>A has been reported in the literature in sequencing studies originating from Korea and Japan among cases affected with Breast and Ovarian Cancer and in control individuals (Park_2016, Momozawa_2018, Choi_2018, Arai_2018). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. At-least one of these reports cites the co-occurrence of this variant among individual(s) with pathogenic BRCA mutations although the co-occuring alteration is not explicitly specified (Choi_2018). This finding provides further supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories have classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
Color RCV000222179 SCV000911460 uncertain significance Hereditary cancer-predisposing syndrome 2018-10-26 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000077339 SCV000109136 uncertain significance Breast-ovarian cancer, familial 2 2011-10-14 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000077339 SCV000146494 uncertain significance Breast-ovarian cancer, familial 2 2004-02-20 no assertion criteria provided clinical testing

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