Submissions for variant NM_007294.4(BRCA1):c.1315G>T (p.Ala439Ser)

dbSNP: rs1064794098

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000481813	SCV000567818	uncertain significance	not provided	2015-09-03	criteria provided, single submitter	clinical testing	This variant is denoted BRCA1 c.1315G>T at the cDNA level, p.Ala439Ser (A439S) at the protein level, and results in the change of an Alanine to a Serine (GCT>TCT). Using alternate nomenclature, this variant would be defined as BRCA1 1434G>T. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA1 Ala439Ser 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 Alanine and Serine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA1 Ala439Ser occurs at a position that is not conserved and is located in multiple functional domains (Paul 2014). 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 Ala439Ser is pathogenic or benign. We consider it to be a variant of uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000690913	SCV000818644	uncertain significance	Hereditary breast ovarian cancer syndrome	2023-01-19	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 439 of the BRCA1 protein (p.Ala439Ser). 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: 419772). 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. 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.
Ambry Genetics	RCV002383919	SCV002691706	uncertain significance	Hereditary cancer-predisposing syndrome	2021-12-30	criteria provided, single submitter	clinical testing	The p.A439S variant (also known as c.1315G>T), located in coding exon 9 of the BRCA1 gene, results from a G to T substitution at nucleotide position 1315. The alanine at codon 439 is replaced by serine, an amino acid with similar properties. This amino acid position is not well conserved in available vertebrate species. 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.
University of Washington Department of Laboratory Medicine, University of Washington	RCV002383919	SCV003846020	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).