Submissions for variant NM_007294.4(BRCA1):c.2929C>T (p.Pro977Ser)

dbSNP: rs1064794043

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000486609	SCV000567662	uncertain significance	not provided	2015-08-10	criteria provided, single submitter	clinical testing	This variant is denoted BRCA1 c.2929C>T at the cDNA level, p.Pro977Ser (P977S) 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 3048C>T. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA1 Pro977Ser 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 Pro977Ser occurs at a position that is not conserved and is located within the RAD51 binding domain (Chen 1998). In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available information, it is unclear whether BRCA1 Pro977Ser is pathogenic or benign. We consider it to be a variant of uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001300935	SCV001490086	uncertain significance	Hereditary breast ovarian cancer syndrome	2022-10-13	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: 419688). 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 977 of the BRCA1 protein (p.Pro977Ser).
Ambry Genetics	RCV002436534	SCV002752391	uncertain significance	Hereditary cancer-predisposing syndrome	2020-04-27	criteria provided, single submitter	clinical testing	The p.P977S variant (also known as c.2929C>T), located in coding exon 9 of the BRCA1 gene, results from a C to T substitution at nucleotide position 2929. The proline at codon 977 is replaced by serine, an amino acid with similar properties. This amino acid position is poorly 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.
University of Washington Department of Laboratory Medicine, University of Washington	RCV002436534	SCV003849245	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).