Submissions for variant NM_007294.4(BRCA1):c.4771G>A (p.Gly1591Ser)

gnomAD frequency: 0.00003  dbSNP: rs587782825

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000132402	SCV000187494	uncertain significance	Hereditary cancer-predisposing syndrome	2021-10-26	criteria provided, single submitter	clinical testing	The p.G1591S variant (also known as c.4771G>A), located in coding exon 14 of the BRCA1 gene, results from a G to A substitution at nucleotide position 4771. The glycine at codon 1591 is replaced by serine, an amino acid with similar properties. In one study, this alteration was detected in 1/705 women with contralateral breast cancer and not in 1398 women with unilateral breast cancer (Borg A et al. Hum. Mutat. 2010 Mar;31:E1200-40). This alteration has been reported in 1/240 hereditary breast and ovarian cancer (HBOC) patients (Schenkel LC et al. J Mol Diagn. 2016 09;18:657-667). 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.
Invitae	RCV000203874	SCV000260007	uncertain significance	Hereditary breast ovarian cancer syndrome	2023-08-23	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: 142926). This missense change has been observed in individual(s) with breast cancer (PMID: 20104584). This variant is present in population databases (rs587782825, gnomAD 0.002%). This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 1591 of the BRCA1 protein (p.Gly1591Ser).
GeneDx	RCV000588705	SCV000321435	uncertain significance	not provided	2016-06-15	criteria provided, single submitter	clinical testing	This variant is denoted BRCA1 c.4771G>A at the cDNA level, p.Gly1591Ser (G1591S) at the protein level, and results in the change of a Glycine to a Serine (GGC>AGC). This variant, defined as BRCA1 4890G>A using alternate nomenclature, was observed in one case of contralateral breast cancer (Borg 2010). BRCA1 Gly1591Ser 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 Glycine and Serine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA1 Gly1591Ser occurs at a position that is not conserved and is located in a region known to interact with multiple proteins (Paul 2014). In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available evidence, it is unclear whether BRCA1 Gly1591Ser is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000588705	SCV000699174	uncertain significance	not provided	2016-12-27	criteria provided, single submitter	clinical testing	Variant summary: The c.4771G>A (p.Gly1591Ser) in BRCA1 gene is a missense change that involves a non-conserved nucleotide and 3/5 in silico tools predict benign outcome. The variant is present in the control population dataset of ExAC at a frequency of 0.000008 (1/121362 chrs tested). The variant is also reported in control population of gnomAD at a frequency of 0.00001 (3/282554 chrs tested), exclusively in individuals of European descent. However, since the resource is still in early beta mode, the occurrences were not captured in pbGP. The observed frequencies do not exceed the maximum expected allele frequency for a pathogenic variant of 0.001. The variant has been reported in affected individuals without strong evidence of causality. In addition, the variant is cited as VUS by several reputable databases/clinical laboratories without evidence to independently evaluate. Taking together, the variant was classified as VUS.
Color Diagnostics, LLC DBA Color Health	RCV000132402	SCV000909011	uncertain significance	Hereditary cancer-predisposing syndrome	2023-03-22	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with serine at codon 1591 of the BRCA1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in a breast cancer case-control meta-analysis in 3/60466 cases and 0/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA1_006205) and an individual affected with breast cancer (PMID: 20104584). A multifactorial analysis has reported likelihood ratios for pathogenicity based on co-occurrence with a pathogenic variant and family history of 1.0331 and 0.4921, respectively (PMID: 31131967). This variant has been identified in 3/282778 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000588705	SCV004219424	uncertain significance	not provided	2023-01-03	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.000023 (3/129102 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in an individual with contralateral breast cancer (PMID: 20104584 (2010), 21520273 (2011)), and in an individual with hereditary breast and ovarian cancer (PMID: 27376475 (2016)). In a large breast cancer association study, the variant was also found in individuals affected with breast cancer (PMID: 33471991 (2021)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant.