Submissions for variant NM_007294.4(BRCA1):c.3169A>G (p.Ser1057Gly)

gnomAD frequency: 0.00001  dbSNP: rs80357479

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000509657	SCV000607757	uncertain significance	Hereditary cancer-predisposing syndrome	2022-04-22	criteria provided, single submitter	clinical testing	The p.S1057G variant (also known as c.3169A>G), located in coding exon 9 of the BRCA1 gene, results from an A to G substitution at nucleotide position 3169. The serine at codon 1057 is replaced by glycine, an amino acid with similar properties. This variant was identified in a cohort of 3,579 African males diagnosed with prostate cancer who underwent multi-gene panel testing of 19 DNA repair and cancer predisposition genes (Matejcic M et al. JCO Precis Oncol, 2020 Jan;4:32-43). This amino acid position is highly 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.
Color Diagnostics, LLC DBA Color Health	RCV000509657	SCV000688423	uncertain significance	Hereditary cancer-predisposing syndrome	2022-05-09	criteria provided, single submitter	clinical testing	This missense variant replaces serine with glycine at codon 1057 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 an individual affected with breast cancer (PMID: 32866190). This variant has been identified in 3/282246 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001328036	SCV000699007	uncertain significance	not specified	2021-03-04	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.3169A>G (p.Ser1057Gly) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 250852 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.3169A>G has been reported in the literature in individuals/families affected with Hereditary Breast And Ovarian Cancer Syndrome (e.g. Judkins_2005, Bishop_2020). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000587239	SCV000887661	uncertain significance	not provided	2018-11-12	criteria provided, single submitter	clinical testing
Invitae	RCV001325551	SCV001516546	uncertain significance	Hereditary breast ovarian cancer syndrome	2023-11-15	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with glycine, which is neutral and non-polar, at codon 1057 of the BRCA1 protein (p.Ser1057Gly). This variant is present in population databases (rs80357479, gnomAD 0.004%). This missense change has been observed in individual(s) with breast cancer (PMID: 32866190). ClinVar contains an entry for this variant (Variation ID: 54787). 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 with a negative predictive value of 95%. 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	RCV000509657	SCV003852529	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).
Sharing Clinical Reports Project (SCRP)	RCV000077539	SCV000109340	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2008-10-14	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000077539	SCV000144652	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2004-11-25	no assertion criteria provided	clinical testing