Submissions for variant NM_007294.4(BRCA1):c.3080G>A (p.Ser1027Asn)

dbSNP: rs80357386

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000481809	SCV000564732	uncertain significance	not provided	2015-01-19	criteria provided, single submitter	clinical testing	This variant is denoted BRCA1 c.3080G>A at the cDNA level, p.Ser1027Asn (S1027N) at the protein level, and results in the change of a Serine to an Asparagine (AGC>AAC). Using alternate nomenclature, this variant would be defined as BRCA1 3199G>A. Evolutionary conservation models have been applied to this variant to predict its effect, with inconsistent results (Fleming 2003, Pavlicek 2004, Burk-Herrick 2006). BRCA1 Ser1027Asn 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 Serine and Asparagine share similar properties, this is considered a conservative amino acid substitution. BRCA1 Ser1027Asn occurs at a position that is well conserved through mammals and is located in the DNA binding domain (Narod 2004). 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 Ser1027Asn is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae	RCV001363320	SCV001559426	uncertain significance	Hereditary breast ovarian cancer syndrome	2022-10-21	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 1027 of the BRCA1 protein (p.Ser1027Asn). 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: 54767). This missense change has been observed in individual(s) with breast cancer (PMID: 10923033). This variant is not present in population databases (gnomAD no frequency).
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001800360	SCV002046306	uncertain significance	not specified	2020-10-15	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002319435	SCV002608868	uncertain significance	Hereditary cancer-predisposing syndrome	2023-02-21	criteria provided, single submitter	clinical testing	The p.S1027N variant (also known as c.3080G>A), located in coding exon 9 of the BRCA1 gene, results from a G to A substitution at nucleotide position 3080. The serine at codon 1027 is replaced by asparagine, an amino acid with highly similar properties. Using a comparative evolutionary approach, one study predicted that this missense alteration affects protein function because it occurs at a conservative site (Fleming MA et al. Proc Natl Acad Sci U S A, 2003 Feb;100:1151-6). This alteration was classified as uncertain significance based on a multifactorial analysis model of variant classification (Parsons MT et al. Hum Mutat, 2019 09;40:1557-1578). This amino acid position is well 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	RCV002319435	SCV003849140	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)	RCV000111995	SCV000144628	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1		no assertion criteria provided	clinical testing