Submissions for variant NM_007294.4(BRCA1):c.1639A>C (p.Asn547His)

gnomAD frequency: 0.00001  dbSNP: rs1060502351

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000456718	SCV000549383	uncertain significance	Hereditary breast ovarian cancer syndrome	2022-08-04	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: 409349). This variant has not been reported in the literature in individuals affected with BRCA1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces asparagine, which is neutral and polar, with histidine, which is basic and polar, at codon 547 of the BRCA1 protein (p.Asn547His).
Ambry Genetics	RCV000510112	SCV000607997	uncertain significance	Hereditary cancer-predisposing syndrome	2021-11-30	criteria provided, single submitter	clinical testing	The p.N547H variant (also known as c.1639A>C), located in coding exon 9 of the BRCA1 gene, results from an A to C substitution at nucleotide position 1639. The asparagine at codon 547 is replaced by histidine, 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 tolerated 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	RCV000590361	SCV000698880	uncertain significance	not provided	2016-01-14	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000590361	SCV000887630	uncertain significance	not provided	2018-04-06	criteria provided, single submitter	clinical testing
University of Washington Department of Laboratory Medicine, University of Washington	RCV000510112	SCV003851154	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.	RCV003316568	SCV004018685	likely benign	Breast-ovarian cancer, familial, susceptibility to, 1	2023-06-23	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].