Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM1
The NM_007294.4(BRCA1):c.4988T>A(p.Met1663Lys) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000823 in 1,457,250 control chromosomes in the GnomAD database, with no homozygous occurrence. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).
BRCA1 (HGNC:1100): (BRCA1 DNA repair associated) This gene encodes a 190 kD nuclear phosphoprotein that plays a role in maintaining genomic stability, and it also acts as a tumor suppressor. The BRCA1 gene contains 22 exons spanning about 110 kb of DNA. The encoded protein combines with other tumor suppressors, DNA damage sensors, and signal transducers to form a large multi-subunit protein complex known as the BRCA1-associated genome surveillance complex (BASC). This gene product associates with RNA polymerase II, and through the C-terminal domain, also interacts with histone deacetylase complexes. This protein thus plays a role in transcription, DNA repair of double-stranded breaks, and recombination. Mutations in this gene are responsible for approximately 40% of inherited breast cancers and more than 80% of inherited breast and ovarian cancers. Alternative splicing plays a role in modulating the subcellular localization and physiological function of this gene. Many alternatively spliced transcript variants, some of which are disease-associated mutations, have been described for this gene, but the full-length natures of only some of these variants has been described. A related pseudogene, which is also located on chromosome 17, has been identified. [provided by RefSeq, May 2020]
Breast-ovarian cancer, familial, susceptibility to, 1 Uncertain:3Benign:1Other:1
Dec 23, 2003
Breast Cancer Information Core (BIC) (BRCA1)
Significance: Uncertain significance
Review Status: no assertion criteria provided
Collection Method: clinical testing
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Brotman Baty Institute, University of Washington
Significance: not provided
Review Status: no classification provided
Collection Method: in vitro
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Jan 07, 2016
Counsyl
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing
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May 02, 2016
Quest Diagnostics Nichols Institute San Juan Capistrano
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing
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Feb 10, 2011
Sharing Clinical Reports Project (SCRP)
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing
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not provided Uncertain:2
Nov 10, 2017
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing
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Jan 02, 2024
GeneDx
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing
Published functional studies demonstrate no damaging effect with respect to protein stability, protein folding, transcriptional activity, homology directed DNA repair, and phosphopeptide-binding activity (PMID: 20378548, 20516115, 35665744); In silico analysis is inconclusive as to whether the variant alters gene splicing; Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as 5107T>A; This variant is associated with the following publications: (PMID: 17305420, 20516115, 20378548, 16267036, 26778126, 30209399, 35665744, 25348405, 25724305) -
Review Status: criteria provided, single submitter
Collection Method: 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). 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). However, additional RNA studies have demonstrated that this alteration does not result in abnormal splicing in the set of samples tested (Ambry internal data). 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. Based on the available evidence, the clinical significance of this variant remains unclear. -
Apr 30, 2024
Color Diagnostics, LLC DBA Color Health
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: 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. 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 detected in a breast cancer case-control meta-analysis in 1/60466 cases and 0/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA1_000361). 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. -
not specified Uncertain:1
Jun 23, 2022
Genetic Services Laboratory, University of Chicago
Significance: Uncertain significance
Review Status: no assertion criteria provided
Collection Method: clinical testing
DNA sequence analysis of the BRCA1 gene demonstrated a sequence change, c.4988T>A, in exon 16 that results in an amino acid change, p.Met1663Lys. This sequence change has not been described in population databases such as ExAC and gnomAD (dbSNP rs80357205). This sequence change has been reported in the Breast Cancer Information Core (BIC) database (PMID: 10923033). The p.Met1663Lys change affects a moderately conserved amino acid residue located in a domain of the BRCA1 protein that is not known to be functional. In-silico missense pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Met1663Lys substitution and functional studies have been inconclusive about the impact this sequence change has on the function of the BRCA1 protein (PMID: 30209399, 20516115, 20378548, 26778126, 30209399). However, in-silico splice prediction programs indicate this sequence change may affect normal splicing of the BRCA1 gene and an in vitro experimental study showed that it may lead to skipping of exon 16 (PMID: 25724305). Due to insufficient evidences. the clinical significance of the p.Met1663Lys change remains unknown at this time. -
BRCA1-related disorder Uncertain:1
Jun 21, 2023
PreventionGenetics, part of Exact Sciences
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing
The BRCA1 c.4988T>A variant is predicted to result in the amino acid substitution p.Met1663Lys. This variant was observed in the Breast Cancer Information Core (BIC) database (Szabo et al. 2000. PubMed ID: 10923033). This variant is interpreted as benign/uncertain in two studies of variant classification (Table S2, Findlay et al. 2018. PubMed ID: 30209399; Table 2, Judkins et al. 2005. PubMed ID: 16267036). Functional studies suggest that p.Met1663Lys variant does not affect the stability of the protein and has low functional effect (Figure 2, Rowling et al. 2010. PubMed ID: 20378548; Table 2, Lee et al. 2010. PubMed ID: 20516115). RT-PCR analysis suggests this variant predominantly leads to exon 17 skipping (Figure 2B, Ahlborn et al. 2015. PubMed ID: 25724305). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. In ClinVar, this variant is interpreted as likely benign/uncertain (https://preview.ncbi.nlm.nih.gov/clinvar/variation/55349/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -
Hereditary breast ovarian cancer syndrome Uncertain:1
Jan 23, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing
This sequence change replaces methionine, which is neutral and non-polar, with lysine, which is basic and polar, at codon 1663 of the BRCA1 protein (p.Met1663Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of BRCA1-related conditions (PMID: 10923033). ClinVar contains an entry for this variant (Variation ID: 55349). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. Experimental studies have shown that this missense change affects BRCA1 function (PMID: 30209399). Studies have shown that this missense change alters mRNA splicing and is expected to lead to the loss of protein expression (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. -