Submissions for variant NM_007294.4(BRCA1):c.1568T>G (p.Leu523Trp)

dbSNP: rs397508885

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000047527	SCV000075540	uncertain significance	Hereditary breast ovarian cancer syndrome	2023-09-22	criteria provided, single submitter	clinical testing	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. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt BRCA1 protein function. ClinVar contains an entry for this variant (Variation ID: 54295). This variant is also known as 1687T>G. This missense change has been observed in individual(s) with breast cancer (PMID: 15735322). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces leucine, which is neutral and non-polar, with tryptophan, which is neutral and slightly polar, at codon 523 of the BRCA1 protein (p.Leu523Trp).
Ambry Genetics	RCV000129756	SCV000184563	uncertain significance	Hereditary cancer-predisposing syndrome	2021-08-27	criteria provided, single submitter	clinical testing	The p.L523W variant (also known as c.1568T>G), located in coding exon 9 of the BRCA1 gene, results from a T to G substitution at nucleotide position 1568. The leucine at codon 523 is replaced by tryptophan, an amino acid with similar properties. This alteration has been described as a novel alteration of unknown significance in a familial breast cancer cohort (Frost et al. Dis Markers. 2005;21(1):29-36). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Color Diagnostics, LLC DBA Color Health	RCV000129756	SCV000909375	uncertain significance	Hereditary cancer-predisposing syndrome	2023-06-22	criteria provided, single submitter	clinical testing	This missense variant replaces leucine with tryptophan at codon 523 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). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with breast cancer in the literature (PMID: 15735322). 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.
GeneDx	RCV001753466	SCV001985987	uncertain significance	not provided	2019-08-09	criteria provided, single submitter	clinical testing	Observed in one or more individuals with a personal history of breast cancer (Frost 2005); Not observed in large population cohorts (Lek 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Also known as BRCA1 1687T>G; This variant is associated with the following publications: (PMID: 15735322)
University of Washington Department of Laboratory Medicine, University of Washington	RCV000129756	SCV003851203	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).
Myriad Genetics, Inc.	RCV003335081	SCV004043175	likely benign	Breast-ovarian cancer, familial, susceptibility to, 1	2023-08-17	criteria provided, single submitter	clinical testing	This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752].
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000047527	SCV004228143	uncertain significance	Hereditary breast ovarian cancer syndrome	2023-10-03	criteria provided, single submitter	clinical testing