ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.4661G>C (p.Ser1554Thr) (rs876661225)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 2
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000214343 SCV000279838 uncertain significance not provided 2016-01-28 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.4661G>C at the cDNA level, p.Ser1554Thr (S1554T) at the protein level, and results in the change of a Serine to a Threonine (AGT>ACT). Using alternate nomenclature, this variant would be defined as BRCA2 4889G>C. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA2 Ser1554Thr 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 Serine and Threonine share similar properties, this is considered a conservative amino acid substitution. BRCA2 Ser1554Thr occurs at a position that is not conserved and is located within the region required for stimulation of POLH DNA polymerization activity (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 Ser1554Thr is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000823127 SCV000963972 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-07-13 criteria provided, single submitter clinical testing This sequence change replaces serine with threonine at codon 1554 of the BRCA2 protein (p.Ser1554Thr). The serine residue is weakly conserved and there is a small physicochemical difference between serine 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: 234801). 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 tolerated, 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.

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.