Submissions for variant NM_007294.4(BRCA1):c.1757C>T (p.Pro586Leu)

dbSNP: rs1064795270

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001955872	SCV002221130	uncertain significance	Hereditary breast ovarian cancer syndrome	2022-03-18	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. 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 proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 586 of the BRCA1 protein (p.Pro586Leu).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002282663	SCV002570842	uncertain significance	not specified	2022-07-29	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.1757C>T (p.Pro586Leu) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251004 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1757C>T has been reported in the literature as somatic occurrence in an individual affected with ovarian cancer. The same individual also carried a potentially germline pathogenic BRCA2 variant (c.5164_5165del, p.Ser1722fs) (Yao_2022). This report does not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. A ClinVar submitter (evaluation after 2014) cites the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Ambry Genetics	RCV002397990	SCV002711685	uncertain significance	Hereditary cancer-predisposing syndrome	2022-04-02	criteria provided, single submitter	clinical testing	The p.P586L variant (also known as c.1757C>T), located in coding exon 9 of the BRCA1 gene, results from a C to T substitution at nucleotide position 1757. The proline at codon 586 is replaced by leucine, an amino acid with similar properties. This amino acid position is conserved. 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.
University of Washington Department of Laboratory Medicine, University of Washington	RCV002397990	SCV003851061	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).