Submissions for variant NM_007294.4(BRCA1):c.1717T>C (p.Ser573Pro)

dbSNP: rs876660448

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000215894	SCV000277881	uncertain significance	Hereditary cancer-predisposing syndrome	2022-03-11	criteria provided, single submitter	clinical testing	The p.S573P variant (also known as c.1717T>C), located in coding exon 9 of the BRCA1 gene, results from a T to C substitution at nucleotide position 1717. The serine at codon 573 is replaced by proline, an amino acid with similar properties. This amino acid position is 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	RCV000590339	SCV000698883	uncertain significance	not provided	2017-07-27	criteria provided, single submitter	clinical testing	Variant summary: The BRCA1 c.1717T>C (p.Ser573Pro) variant involves the alteration of a non-conserved nucleotide that is not located in a known functional domain (InterPro). 3/5 in silico tools predict a benign outcome for this variant. This variant is absent in 121116 control chromosomes tested (ExAC). One clinical diagnostic laboratory has classified this variant as one of uncertain significance in ClinVar. The variant was also reported in one HBOC patient in the UMD database and co-occurred with a likely pathogenic BRCA2 variant (c.8364G>A; p.Trp2788X), suggesting a benign impact for the variant of interest. To our knowledge, the variant of interest has not been reported in affected individuals via publications, nor has it been evaluated for functional impact by in vivo/vitro studies. Taken together, this variant is classified as VUS.
Labcorp Genetics (formerly Invitae), Labcorp	RCV002295293	SCV002596682	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-01-04	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 573 of the BRCA1 protein (p.Ser573Pro). This variant is not present in population databases (gnomAD no frequency). 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: 233500). 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 with a negative predictive value of 95%. 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.
University of Washington Department of Laboratory Medicine, University of Washington	RCV000215894	SCV003851086	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).