Submissions for variant NM_007294.4(BRCA1):c.1709C>A (p.Pro570Gln)

dbSNP: rs879254020

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000759496	SCV000293197	uncertain significance	not provided	2024-04-08	criteria provided, single submitter	clinical testing	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; Has not been previously published as pathogenic or benign to our knowledge; Also known as 1828C>A; This variant is associated with the following publications: (PMID: 29884841, 15343273)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000524967	SCV000635809	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-10-23	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with glutamine, which is neutral and polar, at codon 570 of the BRCA1 protein (p.Pro570Gln). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This variant has not been reported in the literature in individuals affected with BRCA1-related conditions. ClinVar contains an entry for this variant (Variation ID: 245965). 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 not expected to disrupt BRCA1 protein function with a negative 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	RCV000759496	SCV000888845	uncertain significance	not provided	2023-12-17	criteria provided, single submitter	clinical testing	The BRCA1 c.1709C>A (p.Pro570Gln) variant has been observed in a reportedly healthy individual in a breast cancer association study (see LOVD (http://databases.lovd.nl/shared/) and PMID: 33471991 (2021)). This variant has also been reported to be located in a region of the BRCA1 gene that is tolerant to missense sequence changes (PMID: 31911673 (2020)). The frequency of this variant in the general population, 0.000004 (1/250492 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 predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant.
Color Diagnostics, LLC DBA Color Health	RCV000771381	SCV000903705	uncertain significance	Hereditary cancer-predisposing syndrome	2019-05-16	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000771381	SCV001173338	uncertain significance	Hereditary cancer-predisposing syndrome	2024-04-07	criteria provided, single submitter	clinical testing	The p.P570Q variant (also known as c.1709C>A), located in coding exon 9 of the BRCA1 gene, results from a C to A substitution at nucleotide position 1709. The proline at codon 570 is replaced by glutamine, an amino acid with similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001797692	SCV002041728	uncertain significance	not specified	2021-11-11	criteria provided, single submitter	clinical testing
University of Washington Department of Laboratory Medicine, University of Washington	RCV000771381	SCV003851097	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).
All of Us Research Program, National Institutes of Health	RCV004804957	SCV005428608	uncertain significance	BRCA1-related cancer predisposition	2024-08-23	criteria provided, single submitter	clinical testing	This missense variant replaces proline with glutamine at codon 570 of the BRCA1 protein. Computational prediction suggests that this variant may not impact protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with BRCA1-related disorders in the literature. This variant has been identified in 1/250492 chromosomes 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.