ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.1228G>A (p.Ala410Thr) (rs779974365)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 4
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000766408 SCV000294008 uncertain significance not provided 2016-02-29 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.1228G>A at the cDNA level, p.Ala410Thr (A410T) 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 BRCA1 c.1347G>A. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA1 Ala410Thr 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. BRCA1 Ala410Thr occurs at a position that is not conserved and is located in a binding domain known to interact with multiple proteins (Zhang 1998, Chai 1999, Narod 2004, Harte 2010, Zhong 1999). In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available evidence, it is unclear whether BRCA1 Ala410Thr is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000236916 SCV000600242 uncertain significance not specified 2016-12-30 criteria provided, single submitter clinical testing
Ambry Genetics RCV000567869 SCV000668456 uncertain significance Hereditary cancer-predisposing syndrome 2016-11-29 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Invitae RCV000810492 SCV000950695 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-11-21 criteria provided, single submitter clinical testing This sequence change replaces alanine with threonine at codon 410 of the BRCA1 protein (p.Ala410Thr). The alanine residue is moderately conserved and there is a small physicochemical difference between alanine and threonine. This variant is present in population databases (rs779974365, ExAC 0.01%). This variant has been reported in individuals in the Leiden Open-source Variation Database (PMID: 21520333). ClinVar contains an entry for this variant (Variation ID: 246448). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; 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.

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.