Submissions for variant NM_007294.4(BRCA1):c.457A>G (p.Ser153Gly)

dbSNP: rs28897674

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000123278	SCV000166585	uncertain significance	Hereditary breast ovarian cancer syndrome	2022-10-04	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 153 of the BRCA1 protein (p.Ser153Gly). This variant is present in population databases (rs28897674, gnomAD 0.002%). This missense change has been observed in individual(s) with a personal and/or family history of breast and ovarian cancer (PMID: 24010542, 30254663). ClinVar contains an entry for this variant (Variation ID: 96934). 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000758834	SCV000887702	uncertain significance	not provided	2023-05-30	criteria provided, single submitter	clinical testing	In the published literature, this variant has been reported in individuals with a personal and/or family history of breast and/or ovarian cancer (PMID: 25186627 (2015), 24010542 (2014)). The frequency of this variant in the general population, 0.000026 (3/113708 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. 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.
Color Diagnostics, LLC DBA Color Health	RCV000776316	SCV000911641	uncertain significance	Hereditary cancer-predisposing syndrome	2023-05-05	criteria provided, single submitter	clinical testing	This missense variant replaces serine with glycine at codon 153 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 ab individual affected with breast or ovarian cancer (PMID: 24010542) and has been detected in a breast cancer case-control meta-analysis in 1/60466 cases and 0/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA1_001326). This variant has been identified in 3/251428 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.
Ambry Genetics	RCV000776316	SCV002637017	uncertain significance	Hereditary cancer-predisposing syndrome	2022-06-06	criteria provided, single submitter	clinical testing	The p.S153G variant (also known as c.457A>G), located in coding exon 6 of the BRCA1 gene, results from an A to G substitution at nucleotide position 457. The serine at codon 153 is replaced by glycine, an amino acid with similar properties. This variant was reported in multiple individuals diagnosed with breast and/or ovarian cancer (Konstantopoulou I et al. Clin. Genet. 2014 Jan;85:36-42; Tung N et al. Cancer, 2015 Jan;121:25-33; Zuntini R et al. Front Genet, 2018 Sep;9:378). This amino acid position is not 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.
Sharing Clinical Reports Project (SCRP)	RCV000083055	SCV000115129	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2012-05-01	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000500089	SCV000591271	uncertain significance	Malignant tumor of breast		no assertion criteria provided	clinical testing	The p.Ser153Gly variant was not identified in the literature nor was it identified in the NHLBI Exome Sequencing Project (Exome Variant Server), , HGMD, LOVD, COSMIC, GeneInsight VariantWire, the BIC and UMD databases. The variant was identified in the ClinVar database (classified as an uncertain significance variant by the Sharing Clinical Reports Project (derived from Myriad reports) and Invitae); it was also identified in dbSNP (rs28897674), and the Exome Aggregation Consortium (ExAC) database in 2 of 66738 individuals of European background. The p.Ser153Gly residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and 1 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; but this is not very predictive of pathogenicity. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of unknown significance.
Department of Medical and Surgical Sciences, University of Bologna	RCV000083055	SCV004228316	benign	Breast-ovarian cancer, familial, susceptibility to, 1	2023-09-01	no assertion criteria provided	clinical testing	BS3(Strong)+BP1(Strong) according to ACMG/AMP classification guidelines specified for BRCA1 & BRCA2 (Classification Criteria V1.0.0 2023-09-08 - https://cspec.genome.network/cspec/ui/svi/affiliation/50087) (PMID: 38160042)