ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.7883T>C (p.Ile2628Thr) (rs879255465)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000758955 SCV000565768 uncertain significance not provided 2016-05-03 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.7883T>C at the cDNA level, p.Ile2628Thr (I2628T) at the protein level, and results in the change of an Isoleucine to a Threonine (ATA>ACA). Using alternate nomenclature, this variant would be defined as BRCA2 8111T>C. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA2 Ile2628Thr 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 Isoleucine and Threonine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA2 Ile2628Thr occurs at a position where amino acids with properties similar to Isoleucine are tolerated across species and is located in the DNA binding domain as well as a region known to interact with SHFM1 (Marston 1999, Yang 2002) . 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 Ile2628Thr is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000637454 SCV000758914 uncertain significance Hereditary breast and ovarian cancer syndrome 2017-12-18 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with threonine at codon 2628 of the BRCA2 protein (p.Ile2628Thr). The isoleucine residue is moderately conserved and there is a moderate physicochemical difference between isoleucine and threonine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with BRCA2-related disease. ClinVar contains an entry for this variant (Variation ID: 252849). 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 RCV000758955 SCV000887929 uncertain significance not provided 2017-12-15 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000238761 SCV000297452 uncertain significance Breast-ovarian cancer, familial 2 2014-01-08 no assertion criteria provided clinical testing

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