ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.1769T>G (p.Phe590Cys) (rs80358459)

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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 RCV000130772 SCV000185665 uncertain significance Hereditary cancer-predisposing syndrome 2016-07-28 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Breast Cancer Information Core (BIC) (BRCA2) RCV000077265 SCV000145928 uncertain significance Breast-ovarian cancer, familial 2 2002-05-29 no assertion criteria provided clinical testing
Color RCV000130772 SCV000911109 likely benign Hereditary cancer-predisposing syndrome 2017-09-15 criteria provided, single submitter clinical testing
Counsyl RCV000077265 SCV000488000 uncertain significance Breast-ovarian cancer, familial 2 2015-12-11 criteria provided, single submitter clinical testing
GeneDx RCV000486075 SCV000566611 uncertain significance not provided 2018-01-15 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.1769T>G at the cDNA level, p.Phe590Cys (F590C) at the protein level, and results in the change of a Phenylalanine to a Cysteine (TTT>TGT). Using alternate nomenclature, this variant would be defined as BRCA2 1997T>G. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA2 Phe590Cys was not observed at a significant frequency in large population cohorts (Lek 2016). BRCA2 Phe590Cys is not located in a known functional domain. 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 Phe590Cys is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000780024 SCV000917027 uncertain significance not specified 2018-09-28 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.1769T>G (p.Phe590Cys) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 244108 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1769T>G has been reported in the literature in an individual affected with Hereditary Breast and Ovarian Cancer who was indicated to carry another pathogenic variant, although the variant was not specified (Azzollini_2016). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in normal activity using multiple independent measures namely, complementation by BRCA2 variants of the cell lethal phenotype imposed by Cre-mediated loss of Brca2; HDR capacity, as measured by the repair of I-Sce1 induced double strand breaks (DSBs); and Cisplatin sensitivity of BRCA2 variants (Meman_2018). Four ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cites the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
Invitae RCV000043879 SCV000071892 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-12-04 criteria provided, single submitter clinical testing This sequence change replaces phenylalanine with cysteine at codon 590 of the BRCA2 protein (p.Phe590Cys). The phenylalanine residue is highly conserved and there is a large physicochemical difference between phenylalanine and cysteine. This variant is present in population databases (rs80358459, ExAC 0.003%). This variant has been reported in an individual identified as being at high risk for hereditary breast and ovarian cancer syndrome (PMID: 27062684). This variant has also been reported in individuals in the Breast Cancer Information Core database (PMID: 10923033). ClinVar contains an entry for this variant (Variation ID: 51189). 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 disruptive, 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.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000486075 SCV000887759 uncertain significance not provided 2018-04-25 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000077265 SCV000109062 benign Breast-ovarian cancer, familial 2 2012-05-01 no assertion criteria provided clinical testing

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