Submissions for variant NM_007294.4(BRCA1):c.943A>G (p.Arg315Gly)

dbSNP: rs80357050

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000481816	SCV000570228	uncertain significance	not provided	2016-05-03	criteria provided, single submitter	clinical testing	This variant is denoted BRCA1 c.943A>G at the cDNA level, p.Arg315Gly (R315G) at the protein level, and results in the change of an Arginine to a Glycine (AGG>GGG). Using alternate nomenclature, this variant would be defined as BRCA1 1062A>G. This variant was observed in at least one African American individual with breast cancer (Olopade 2003). BRCA1 Arg315Gly was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Arginine and Glycine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA1 Arg315Gly occurs at a position that is not conserved and is located in the region known for interaction with multiple proteins (Paul 2014). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether BRCA1 Arg315Gly is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae	RCV001315064	SCV001505620	uncertain significance	Hereditary breast ovarian cancer syndrome	2022-06-13	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 315 of the BRCA1 protein (p.Arg315Gly). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of BRCA1-related conditions (PMID: 12491487, 16267036). ClinVar contains an entry for this variant (Variation ID: 55761). 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. RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (Invitae). 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	RCV003157389	SCV003846277	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).
Breast Cancer Information Core (BIC) (BRCA1)	RCV000111514	SCV000143957	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1		no assertion criteria provided	clinical testing