Submissions for variant NM_007294.4(BRCA1):c.1357G>C (p.Glu453Gln)

gnomAD frequency: 0.00002  dbSNP: rs768054411

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000586479	SCV000572888	uncertain significance	not provided	2017-01-26	criteria provided, single submitter	clinical testing	This variant is denoted BRCA1 c.1357G>C at the cDNA level, p.Glu453Gln (E453Q) at the protein level, and results in the change of a Glutamic Acid to a Glutamine (GAG>CAG). Using alternate nomenclature, this variant would be defined as BRCA1 1476G>C. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA1 Glu453Gln was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Glutamic Acid and Glutamine differ in some properties, this is considered a semi-conservative amino acid substitution. BRCA1 Glu453Gln occurs at a position that is not conserved and is located in the DNA binding domain and the region known to interact with multiple proteins (Narod 2004, Paul 2014). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether BRCA1 Glu453Gln is pathogenic or benign. We consider it to be a variant of uncertain significance.
Ambry Genetics	RCV000573359	SCV000665838	likely benign	Hereditary cancer-predisposing syndrome	2019-07-01	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000586479	SCV000698852	uncertain significance	not provided	2017-04-21	criteria provided, single submitter	clinical testing	Variant summary: The BRCA1 c.1357G>C (p.Glu453Gln) variant involves the alteration of a non-conserved nucleotide, predicted to be damaging by 2/4 in silico tools (SNPs&GO not captured due to low reliability index), and is located in Serine Rich (S-R) domain of the protein. This variant was found in 1/121328 control chromosomes from ExAC at a frequency of 0.0000082, which does not exceed the estimated maximal expected allele frequency of a pathogenic BRCA1 variant (0.0010005). The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases/clinical diagnostic laboratories, nor evaluated for functional impact by in vivo/vitro studies. Nearby region of this codon is not highly clustered with disease-causing mutations (ref. HGMD). Because of the absence of clinical information and the lack of functional studies, the variant is classified as a variant of uncertain significance (VUS) until additional information becomes available.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000637435	SCV000758894	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-10-30	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with glutamine, which is neutral and polar, at codon 453 of the BRCA1 protein (p.Glu453Gln). This variant is present in population databases (rs768054411, gnomAD 0.006%). This missense change has been observed in individual(s) with hereditary breast and/or ovarian cancer (PMID: 29176636, 30287823, 31907386, 32803532, 33875706). ClinVar contains an entry for this variant (Variation ID: 423223). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt BRCA1 protein function with a positive predictive value of 80%. 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000586479	SCV001470371	uncertain significance	not provided	2023-08-09	criteria provided, single submitter	clinical testing	In the published literature, this variant has been reported in individuals with breast cancer (PMID: 33875706 (2021), 33471991 (2021), 32803532 (2020), 30287823 (2018)), prostate cancer (PMID: 31214711 (2020)), and bladder cancer (PMID: 34232950 (2021)). This variant has also been reported in unaffected individuals (PMID: 32467295 (2020), 31214711 (2020), 30287823 (2018)). The frequency of this variant in the general population, 0.00002 (3/152194 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is benign or damaging. Based on the available information, we are unable to determine the clinical significance of this variant.
University of Washington Department of Laboratory Medicine, University of Washington	RCV000573359	SCV003851349	likely benign	Hereditary cancer-predisposing syndrome	2023-03-23	criteria provided, single submitter	curation	Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673).