ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.4333C>A (p.Pro1445Thr) (rs876660684)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 3
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000219259 SCV000278314 uncertain significance Hereditary cancer-predisposing syndrome 2015-09-14 criteria provided, single submitter clinical testing
GeneDx RCV000255891 SCV000321434 uncertain significance not provided 2017-03-21 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.4333C>A at the cDNA level, p.Pro1445Thr (P1445T) at the protein level, and results in the change of a Proline to a Threonine (CCA>ACA). Using alternate nomenclature, this variant would be defined as BRCA1 4452C>A. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA1 Pro1445Thr was not observed in in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Proline and Threonine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA1 Pro1445Thr occurs at a position that is not conserved and is located in the SCD domain and a region known to interact with multiple proteins (Narod 2004, Clark 2012, Chen 1998). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available information, it is unclear whether BRCA1 Pro1445Thr is pathogenic or benign. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000781006 SCV000918754 uncertain significance not specified 2018-07-09 criteria provided, single submitter clinical testing Variant summary: BRCA1 c.4333C>A (p.Pro1445Thr) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4.1e-06 in 246144 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.4333C>A in individuals affected with Hereditary Breast and Ovarian Cancer and no experimental evidence demonstrating its impact on protein function have been reported. Two ClinVar submissions from a clinical diagnostic laboratories (evaluation after 2014) cite the variant as "uncertain significance." Based on the evidence outlined above, the variant was classified as 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.