ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.5326C>T (p.Pro1776Ser) (rs1800757)

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
Invitae RCV000477350 SCV000549292 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-05-16 criteria provided, single submitter clinical testing This sequence change replaces proline with serine at codon 1776 of the BRCA1 protein (p.Pro1776Ser). The proline residue is moderately conserved and there is a moderate physicochemical difference between proline and serine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals affected with ovarian cancer (PMID: 15172985, 10196379). ClinVar contains an entry for this variant (Variation ID: 409312). 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.
GeneDx RCV000480229 SCV000565865 uncertain significance not provided 2016-08-03 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.5326C>T at the cDNA level, p.Pro1776Ser (P1776S) at the protein level, and results in the change of a Proline to a Serine (CCC>TCC). Also reported as BRCA1 5445C>T using alternate nomenclature, this variant was observed in an individual with ovarian cancer and no family history of cancer (Janezic 1999). BRCA1 Pro1776Ser was not observed at a significant allele frequency in the NHLBI Exome Sequencing Project. Since Proline and Serine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA1 Pro1776Ser occurs at a position that is not conserved and is located within the BRCT2 domain and a region known to interact with multiple proteins (Paul 2014, UniProt). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, it is unclear whether BRCA1 Pro1776Ser is a pathogenic or benign variant. We consider it to be 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.