Submissions for variant NM_007294.4(BRCA1):c.2689C>T (p.Pro897Ser)

dbSNP: rs770583134

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000478436	SCV000568060	uncertain significance	not provided	2015-09-25	criteria provided, single submitter	clinical testing	This variant is denoted BRCA1 c.2689C>T at the cDNA level, p.Pro897Ser (P897S) at the protein level, and results in the change of a Proline to a Serine (CCA>TCA). Using alternate nomenclature, this variant would be defined as BRCA1 2808C>T. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA1 Pro897Ser was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Proline and Serine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA1 Pro897Ser occurs at a position that is not conserved and is located in the DNA binding domain and a region known to interact with multiple proteins (Narod 2004, Paul 2014). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available information, it is unclear whether BRCA1 Pro897Ser is pathogenic or benign. We consider it to be a variant of uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV002526556	SCV003319285	uncertain significance	Hereditary breast ovarian cancer syndrome	2022-06-07	criteria provided, single submitter	clinical testing	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: 419883). 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 serine, which is neutral and polar, at codon 897 of the BRCA1 protein (p.Pro897Ser). 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	RCV003157574	SCV003849423	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).
Ambry Genetics	RCV003157574	SCV004058447	uncertain significance	Hereditary cancer-predisposing syndrome	2023-08-03	criteria provided, single submitter	clinical testing	The p.P897S variant (also known as c.2689C>T), located in coding exon 9 of the BRCA1 gene, results from a C to T substitution at nucleotide position 2689. The proline at codon 897 is replaced by serine, 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.