ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.4988T>A (p.Met1663Lys) (rs80357205)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 9
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000212190 SCV000883467 uncertain significance not provided 2017-11-10 criteria provided, single submitter clinical testing
Ambry Genetics RCV000509707 SCV000607760 uncertain significance Hereditary cancer-predisposing syndrome 2018-02-02 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Conflicting evidence
Breast Cancer Information Core (BIC) (BRCA1) RCV000112457 SCV000145253 uncertain significance Breast-ovarian cancer, familial 1 2003-12-23 no assertion criteria provided clinical testing
Color RCV000509707 SCV000683235 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-29 criteria provided, single submitter clinical testing
Counsyl RCV000112457 SCV000488121 uncertain significance Breast-ovarian cancer, familial 1 2016-01-07 criteria provided, single submitter clinical testing
GeneDx RCV000212190 SCV000210193 uncertain significance not provided 2017-12-18 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.4988T>A at the cDNA level, p.Met1663Lys (M1663K) at the protein level, and results in the change of a Methionine to a Lysine (ATG>AAG). Using alternate nomenclature, this variant would be defined as BRCA1 5107T>A. Protein based functional studies have demonstrated that this variant does not impact protein structure or function with respect to protein stability, protein folding, transcriptional activity, and phosphopeptide-binding activity (Rowling 2010, Lee 2010). However, splice prediction models indicate that this variant may damage the nature splice acceptor site, possibly causing abnormal gene splicing. Along these lines, Ahlborn et al. (2015) found that BRCA1 Met1663Lys results in significant skipping of exon 16 (reported as exon 17) in an in vitro minigene assay; however, in vivo RNA assays have not been completed. BRCA1 Met1663Lys was not observed in large population cohorts (Lek 2016). Since Methionine and Lysine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA1 Met1663Lys is located in the BRCT1 domain and a region known to interact with multiple other proteins (Narod 2004, Paul 2014). Protein-based in-silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available information, it is unclear whether BRCA1 Met1663Lys is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae RCV000048730 SCV000076743 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-01-07 criteria provided, single submitter clinical testing This sequence change replaces methionine with lysine at codon 1663 of the BRCA1 protein (p.Met1663Lys). The methionine residue is moderately conserved and there is a moderate physicochemical difference between methionine and lysine. This variant is not present in population databases (rs80357205, ExAC no frequency). This variant has been reported in individuals in the Breast Cancer Information Core database (PMID: 10923033). ClinVar contains an entry for this variant (Variation ID: 55349). Experimental studies have shown that this missense change does not effected protein folding, binding activity, binding specificity or transcriptional activation (PMID: 20378548, 20516115). However, another study has shown that this missense change disrupts the dimerization ability of the BRCT domain (PMID: 26778126). Experimental studies have shown that this missense change results in partially altered mRNA splicing and results in exon 16 skipping for a portion of the transcripts (PMID: 25724305). In summary, this variant has been shown to retain many of its protein function, while having partially disrupted dimerization ability and partially altered mRNA splicing. However, the clinical significance of these experimental findings are uncertain and segregation data is not available. For these reasons, this change has been classified as a Variant of Uncertain Significance.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000112457 SCV000296463 uncertain significance Breast-ovarian cancer, familial 1 2016-05-02 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000112457 SCV000297616 likely benign Breast-ovarian cancer, familial 1 2011-02-10 no assertion criteria provided clinical testing

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.