ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.3382A>G (p.Thr1128Ala) (rs730881523)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000215811 SCV000273235 uncertain significance Hereditary cancer-predisposing syndrome 2017-06-06 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Color RCV000215811 SCV000688800 uncertain significance Hereditary cancer-predisposing syndrome 2018-09-20 criteria provided, single submitter clinical testing
GeneDx RCV000766610 SCV000210315 uncertain significance not provided 2016-12-06 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.3382A>G at the cDNA level, p.Thr1128Ala (T1128A) at the protein level, and results in the change of a Threonine to an Alanine (ACT>GCT). Using alternate nomenclature, this variant would be defined as BRCA2 3610A>G. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA2 Thr1128Ala 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 Threonine and Alanine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA2 Thr1128Ala occurs at a position that is conserved across species and is located within the RAD51 binding domain (Roy 2012). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, it is unclear whether BRCA2 Thr1128Ala is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Genetic Services Laboratory, University of Chicago RCV000160063 SCV000593743 uncertain significance not specified 2016-02-23 criteria provided, single submitter clinical testing
Invitae RCV000205030 SCV000261257 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-12-25 criteria provided, single submitter clinical testing This sequence change replaces threonine with alanine at codon 1128 of the BRCA2 protein (p.Thr1128Ala). The threonine residue is highly conserved and there is a small physicochemical difference between threonine and alanine. This variant is present in population databases (rs730881523, ExAC 0.002%). This variant has not been reported in the literature in individuals with BRCA2-related disease. ClinVar contains an entry for this variant (Variation ID: 182200). 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.

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