ClinVar Miner

Submissions for variant NM_000059.4(BRCA2):c.2233A>G (p.Lys745Glu) (rs374691587)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000130703 SCV000185590 likely benign Hereditary cancer-predisposing syndrome 2018-10-30 criteria provided, single submitter clinical testing In silico models in agreement (benign);Insufficient or conflicting evidence;Other strong data supporting benign classification
GeneDx RCV000160045 SCV000210285 likely benign not specified 2017-11-28 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Invitae RCV000197517 SCV000254172 uncertain significance Hereditary breast and ovarian cancer syndrome 2020-09-24 criteria provided, single submitter clinical testing This sequence change replaces lysine with glutamic acid at codon 745 of the BRCA2 protein (p.Lys745Glu). The lysine residue is weakly conserved and there is a small physicochemical difference between lysine and glutamic acid. This variant is present in population databases (rs374691587, ExAC 0.01%). This variant has been reported in individuals affected with breast cancer (PMID: 22034289, 20051372, 26287763). This variant is also known as 2461A>G in the literature. ClinVar contains an entry for this variant (Variation ID: 141961). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: (SIFT: Tolerated; PolyPhen-2: Benign; Align-GVGD: Class C0). The glutamic acid amino acid residue is also found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies. 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.
Counsyl RCV000410547 SCV000488508 uncertain significance Breast-ovarian cancer, familial 2 2016-04-15 criteria provided, single submitter clinical testing
Mendelics RCV000197517 SCV000838768 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-07-02 criteria provided, single submitter clinical testing
Color Health, Inc RCV000130703 SCV000905803 uncertain significance Hereditary cancer-predisposing syndrome 2020-08-19 criteria provided, single submitter clinical testing This missense variant replaces lysine with glutamic acid at codon 745 of the BRCA2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with breast cancer (PMID: 18284688, 22034289). This variant has been identified in 7/282666 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000160045 SCV000916973 uncertain significance not specified 2019-10-04 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.2233A>G (p.Lys745Glu) results in a conservative amino acid change in the encoded protein sequence. Four of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 251266 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2233A>G has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer (Bellacosa_2010, Fackenthal_2012, Lee_2008, Pal_2015). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (4 VUS, 2 likely benign). Based on the evidence outlined above, the variant was classified as uncertain significance.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000985472 SCV001133703 uncertain significance not provided 2019-09-23 criteria provided, single submitter clinical testing
Mendelics RCV000410547 SCV001139025 uncertain significance Breast-ovarian cancer, familial 2 2019-05-28 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000985472 SCV000591795 uncertain significance not provided no assertion criteria provided clinical testing The BRCA2 c.2233A>G variant has not been reported in the literature nor previously identified by our laboratory. This residue is not highly conserved in mammals and the variant amino acid 745Glu is present in mammals. In addition, computational analyses (SIFT, AlignGVGD) do not suggest a high likelihood of impact to the protein. However, this information is not predictive enough to rule out pathogenicity. In summary, based on the above information alone the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. Classified under. ACMG 3

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