Submissions for variant NM_007294.4(BRCA1):c.470C>G (p.Ser157Cys)

gnomAD frequency: 0.00001  dbSNP: rs80357045

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000589839	SCV000293777	uncertain significance	not provided	2018-10-15	criteria provided, single submitter	clinical testing	This variant is denoted BRCA1 c.470C>G at the cDNA level, p.Ser157Cys (S157C) at the protein level, and results in the change of a Serine to a Cysteine (TCT>TGT). Using alternate nomenclature, this variant would be defined as BRCA1 589C>G. This variant has not, to our knowledge, been published in the literature as a pathogenic or benign germline variant. BRCA1 Ser157Cys was not observed in large population cohorts (Lek 2016). This variant is located in the BRD7 binding domain (Harte 2010). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether BRCA1 Ser157Cys is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000589839	SCV000296475	uncertain significance	not provided	2023-08-23	criteria provided, single submitter	clinical testing	In the published literature, this variant has been reported in individuals with breast cancer (PMID: 16267036 (2005), 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/BRCA1)). The frequency of this variant in the general population, 0.0000066 (1/152206 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 conflicting predictions that this variant is benign or damaging. Based on the available information, we are unable to determine the clinical significance of this variant.
Ambry Genetics	RCV000567369	SCV000661135	uncertain significance	Hereditary cancer-predisposing syndrome	2021-05-06	criteria provided, single submitter	clinical testing	The p.S157C variant (also known as c.470C>G), located in coding exon 6 of the BRCA1 gene, results from a C to G substitution at nucleotide position 470. The serine at codon 157 is replaced by cysteine, an amino acid with dissimilar properties. This variant was reported in 3/60,466 breast cancer cases and in 0/53,461 controls (Dorling et al. N Engl J Med. 2021 02;384:428-439). This amino acid position is 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002265585	SCV000699166	uncertain significance	not specified	2022-05-31	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.470C>G (p.Ser157Cys) 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 was absent in 251450 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.470C>G has been reported in the literature in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome without strong evidence for causality (Judkins_2005). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. Co-occurrences with another pathogenic variant have been reported (BRCA1 c.4603G>T, p.Glu1535Ter; BIC), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS - possibly benign.
Counsyl	RCV000112715	SCV000785770	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2017-11-27	criteria provided, single submitter	clinical testing
Invitae	RCV001351686	SCV001546180	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-01-19	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 157 of the BRCA1 protein (p.Ser157Cys). 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: 55266). 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.
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV000112715	SCV003842970	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2022-12-20	criteria provided, single submitter	clinical testing	The BRCA1 c.470C>G (p.Ser157Cys) missense change is absent in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL is inconclusive about a pathogenic or benign effect of this variant on protein function, and to our knowledge functional studies have not been performed. This variant has been reported in 3 of 60,466 individuals with breast cancer and was not found in 53,461 controls (PMID: 33471991). This variant is absent in the FLOSSIES database which contains genetic variants from women older than 70 years of age who have never had cancer (https://whi.color.com/). To our knowledge, this variant has not been reported in individuals with hereditary breast and ovarian cancer or Fanconi anemia. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance.?
Baylor Genetics	RCV000112715	SCV004215102	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2023-06-06	criteria provided, single submitter	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000112715	SCV000145593	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2004-02-20	no assertion criteria provided	clinical testing