ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.4988T>A (p.Met1663Lys) (rs80357205)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000048730 SCV000076743 uncertain significance Hereditary breast and ovarian cancer syndrome 2020-04-21 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 affect protein folding, binding activity, binding specificity or transcriptional activation (PMID: 20378548, 20516115). However, other studies have shown that this missense change disrupts the dimerization ability of the BRCT domain (PMID: 26778126) and results in loss of function in vitro (PMID: 30209399). 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, 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 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.
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
Counsyl RCV000112457 SCV000488121 uncertain significance Breast-ovarian cancer, familial 1 2016-01-07 criteria provided, single submitter clinical testing
Ambry Genetics RCV000509707 SCV000607760 uncertain significance Hereditary cancer-predisposing syndrome 2020-08-14 criteria provided, single submitter clinical testing The p.M1663K variant (also known as c.4988T>A), located in coding exon 15 of the BRCA1 gene, results from a T to A substitution at nucleotide position 4988. The methionine at codon 1663 is replaced by lysine, an amino acid with similar properties. Functional studies and in silico predictions have previously shown that the p.M1663K alteration had low or no functional effect on protein level (Karchin R et al PLoS Comput Biol. 2007;16:3(2):e26; Rowling PJE et al J. Biol. Chem. 2010; 285(26): 20080–20087; Lee MS et al. Cancer Res. 2010; 70:4880-4890). However, In silico splice site analysis predicts that this alteration may weaken the native splice acceptor site, and using an in vitro mini gene assay, Alhborn LB et al. showed that the c.4988T>A (p.M1663K) alteration results in exon 17 skipping that leads to predominant production of an out-of-frame transcript with weak residual wild-type transcript representing only 7% of the total (Alhborn LB et al Breast Cancer Res Treat. 2015; 150(2):289-98). Further, one functional study found that this nucleotide substitution is deleterious in a high throughput genome editing haploid cell survival assay (Findlay GM et al. Nature, 2018 10;562:217-222), and a study using both in vitro and in vivo functional analyses found that this alteration disrupts the ability of BRCT to dimerize (Wu Q et al. Mol. Cell, 2016 Feb;61:434-48). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is conflicting at this time, the clinical significance of this alteration remains unclear.
Color Health, Inc RCV000509707 SCV000683235 uncertain significance Hereditary cancer-predisposing syndrome 2021-02-07 criteria provided, single submitter clinical testing This missense variant replaces methionine with lysine at codon 1663 of the BRCA1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Splice site prediction tools are inconclusive regarding the impact of this variant on RNA splicing. A minigene splicing assay reported the variant resulted in the skipping of exon 16 (BIC exon 17) (PMID: 25724305). Functional studies found conflicting results on the variant protein where it is reported to be normal in protease sensitivity, peptide binding and specificity and transcriptional activation assays (PMID: 20516115, 20378548) but abnormal in BRCT domain dimerization assays (PMID: 26778126) and in a haploid cell proliferation assay (PMID: 30209399). This variant has been reported in the Breast Cancer Information Core (BIC) database (PMID: 10923033) and in an individual with personal history and family history of BRCA1-associated cancer (Color internal data). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000212190 SCV000883467 uncertain significance not provided 2017-11-10 criteria provided, single submitter clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000112457 SCV000145253 uncertain significance Breast-ovarian cancer, familial 1 2003-12-23 no assertion criteria provided 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
Brotman Baty Institute,University of Washington RCV000112457 SCV001242765 not provided Breast-ovarian cancer, familial 1 no assertion provided in vitro

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