ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.5071A>G (p.Thr1691Ala) (rs397509219)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 7
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000589379 SCV000292911 uncertain significance not provided 2016-02-04 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.5071A>G at the cDNA level, p.Thr1691Ala (T1691A) at the protein level, and results in the change of a Threonine to an Alanine (ACA>GCA). This variant, also known as BRCA1 5190A>G using alternate nomenclature, was reported to be associated with RNA similar to wild type in a study of splicing defects using stimulated lymphocytes (Houdayer 2012). BRCA1 Thr1691Ala 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. BRCA1 Thr1691Ala occurs at a position that is conserved in mammals and is located within the BRCT1 domain (UniProt). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available information, it is unclear whether BRCA1 Thr1691Ala is pathogenic or benign. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000573049 SCV000665875 likely benign Hereditary cancer-predisposing syndrome 2020-03-31 criteria provided, single submitter clinical testing In silico models in agreement (benign);Other data supporting benign classification;Rarity in general population databases (dbsnp, esp, 1000 genomes)
Color Health, Inc RCV000573049 SCV000683246 uncertain significance Hereditary cancer-predisposing syndrome 2019-01-04 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000589379 SCV000699197 uncertain significance not provided 2016-07-12 criteria provided, single submitter clinical testing Variant summary: The BRCA1 c.5071A>G (p.Thr1691Ala) variant involves the alteration of a conserved nucleotide located in BRCT domain. p.Thr1691Ala was predicted to destabilize the BRCT domain and could have a functional impact (Caputo_2012). 3/4 in silico tools predict a damaging outcome for this variant (SNPs&GO not captured due to low reliability index). 3/5 splice prediction tools predict no significant impact on normal splicing, which was confirmed by RNA analysis in patient's T lymphoctes (Houdayer_2012). This variant is absent in 121146 control chromosomes. This variant has been reported in patients in literature or databases without convincing evidence supporting pathogenicity of this variant. Taken together, this variant is classified as VUS until more information is available.
Counsyl RCV000662496 SCV000785015 uncertain significance Breast-ovarian cancer, familial 1 2017-03-23 criteria provided, single submitter clinical testing
Invitae RCV001360741 SCV001556673 uncertain significance Hereditary breast and ovarian cancer syndrome 2020-06-01 criteria provided, single submitter clinical testing This sequence change replaces threonine with alanine at codon 1691 of the BRCA1 protein (p.Thr1691Ala). The threonine residue is highly conserved and there is a small physicochemical difference between threonine and alanine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in an individual affected with ovarian cancer (PMID: 24504028). ClinVar contains an entry for this variant (Variation ID: 55371). This variant has been reported to have conflicting or insufficient data to determine the effect on BRCA1 protein function (PMID: 30209399, 30257991). Two different missense substitutions at this codon (p.Thr1691Ile and p.Thr1691Lys) have been reported to have severe effects on BRCA1 protein folding, binding ability, and transcriptional activation (PMID: 20516115, 22277901, 23867111). This suggests that the threonine residue is critical for BRCA1 protein function and that other missense substitutions at this position may also be damaging. 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.
Brotman Baty Institute,University of Washington RCV000662496 SCV001243460 not provided Breast-ovarian cancer, familial 1 no assertion provided in vitro

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.