ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.5309G>T (p.Gly1770Val) (rs863224765)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 5
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) RCV000477771 SCV001161716 pathogenic Breast-ovarian cancer, familial 1 2018-07-18 reviewed by expert panel curation IARC class based on posterior probability from multifactorial likelihood analysis, thresholds for class as per Plon et al. 2008 (PMID: 18951446). Class 5 Pathogenic based on posterior probability = 0.999.
Department of Medical Genetics, Oslo University Hospital RCV000477771 SCV000564383 likely pathogenic Breast-ovarian cancer, familial 1 2016-03-10 criteria provided, single submitter clinical testing
Ambry Genetics RCV001023895 SCV001185836 likely pathogenic Hereditary cancer-predisposing syndrome 2018-05-10 criteria provided, single submitter clinical testing The p.G1770V variant (also known as c.5309G>T), located in coding exon 19 of the BRCA1 gene, results from a G to T substitution at nucleotide position 5309. The glycine at codon 1770 is replaced by valine, an amino acid with dissimilar properties. This alteration has been reported in multiple individuals with personal and/or family history consistent with hereditary breast and ovarian cancer (HBOC) syndrome (Heramb C et al. Hered Cancer Clin Pract, 2018 Jan;16:3) and has been described as a Moroccan founder mutation based on haplotype analysis (Quiles F et al. Clin. Genet., 2016 Oct;90:361-5). Functional studies have shown this alteration results in dramatically compromised transcriptional activity (Quiles F et al. PLoS ONE, 2013 Apr;8:e61302) as well as protein levels consistent with a deleterious mutation based on a cisplatin sensitivity assay (Bouwman P et al. Cancer Discov, 2013 Oct;3:1142-55). A structural analysis study suggests that this alteration results in significant alteration of BRCT structure compromising binding (Quiles F et al. PLoS ONE, 2013 Apr;8:e61302). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000502156 SCV000591610 likely pathogenic Malignant tumor of breast no assertion criteria provided clinical testing The BRCA1 p.Gly1770Val variant was identified in the literature and in HGMD and UMD (9X as an unclassified variant), and was not reported in the 1000 Genomes and Exome Variant Server databases. Although the p.Gly1770 residue is not conserved in mammals, four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the p.Gly1770Val variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. Functional studies by Bouwman (2013) suggest the variant protein levels are associated with structural instability and classifies the variant as deleterious. Furthermore, the amino acid position is located within the C-terminal region of BRCA1 and dramatically compromises the transcriptional activity of BRCA1. Quiles et al (2013) suggests that this variant has significant functional impact and may be pathogenic. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more pathogenic role for this variant. This variant is classified as predicted pathogenic.
Brotman Baty Institute,University of Washington RCV000477771 SCV001242604 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.