ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.4759G>A (p.Ala1587Thr) (rs56137239)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000166660 SCV000217465 likely benign Hereditary cancer-predisposing syndrome 2018-03-29 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Other strong data supporting benign classification,In silico models in agreement (benign)
Color RCV000166660 SCV000688893 uncertain significance Hereditary cancer-predisposing syndrome 2018-09-23 criteria provided, single submitter clinical testing
Counsyl RCV000412143 SCV000489102 uncertain significance Breast-ovarian cancer, familial 2 2016-08-19 criteria provided, single submitter clinical testing
GeneDx RCV000236670 SCV000293727 uncertain significance not provided 2015-12-23 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.4759G>A at the cDNA level, p.Ala1587Thr (A1587T) at the protein level, and results in the change of an Alanine to a Threonine (GCT>ACT). Using alternate nomenclature, this variant would be defined as BRCA2 4987G>A. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA2 Ala1587Thr was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Alanine and Threonine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA2 Ala1587Thr occurs at a position that is not conserved and is located within a region required for POLH DNA synthesis stimulation and for interaction with POLH and RAD51 (Roy 2012, UniProt). In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available evidence, it is unclear whether BRCA2 Ala1587Thr is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000781116 SCV000918957 uncertain significance not specified 2018-09-10 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.4759G>A (p.Ala1587Thr) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 3.2e-05 in 30956 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. The variant, c.4759G>A, has been reported in the literature in one individual affected with Pancreatic Cancer (Grant_2015). This report does 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. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (VUS x3, likely benign x1). Based on the evidence outlined above, the variant was classified as uncertain significance.
Invitae RCV000690936 SCV000818667 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-12-10 criteria provided, single submitter clinical testing This sequence change replaces alanine with threonine at codon 1587 of the BRCA2 protein (p.Ala1587Thr). The alanine residue is weakly conserved and there is a small physicochemical difference between alanine and threonine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in an individual affected with pancreatic cancer (PMID: 25479140). ClinVar contains an entry for this variant (Variation ID: 186987). 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 threonine amino acid residue is 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 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.

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