Submissions for variant NM_007294.4(BRCA1):c.3560G>A (p.Ser1187Asn)

gnomAD frequency: 0.00001  dbSNP: rs80356975

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000048233	SCV000076246	uncertain significance	Hereditary breast ovarian cancer syndrome	2023-10-22	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 1187 of the BRCA1 protein (p.Ser1187Asn). This variant is present in population databases (rs80356975, gnomAD 0.009%). This missense change has been observed in individual(s) with breast cancer and breast cancer and abdominal wall sarcoma (PMID: 21810505, 30287823). This variant is also known as c.3679G>A. ClinVar contains an entry for this variant (Variation ID: 54917). 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	RCV000217356	SCV000273685	uncertain significance	Hereditary cancer-predisposing syndrome	2022-08-24	criteria provided, single submitter	clinical testing	The p.S1187N variant (also known as c.3560G>A), located in coding exon 9 of the BRCA1 gene, results from a G to A substitution at nucleotide position 3560. The serine at codon 1187 is replaced by asparagine, an amino acid with highly similar properties. This alteration was identified in a population-based study of early-onset breast cancer diagnoses (Lee E et al. Breast Cancer Res. 2008 Feb;10:R19). This alteration was also observed in 1/7,051 unselected female breast cancer patients and was not observed in 11,241 female controls of Japanese ancestry (Momozawa Y et al. Nat Commun. 2018 10;9:4083). This alteration was seen in 1/732 breast cancer patients, 0/189 colorectal cancer patients and 0/490 cancer-free elderly controls in a Turkish population (Akcay IM et al. Int J Cancer. 2021 01;148:285-295). 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.
GeneDx	RCV000586582	SCV000292976	uncertain significance	not provided	2019-10-23	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Observed in individuals with breast cancer as well as in an individual with suspected Hereditary Breast and Ovarian Cancer syndrome (Miller-Samuel 2011, Schenkel 2016, Momozawa 2018); This variant is associated with the following publications: (PMID: 30287823, 27376475, 21810505)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000586582	SCV000699041	uncertain significance	not provided	2017-07-07	criteria provided, single submitter	clinical testing	Variant summary: The BRCA1 c.3560G>A (p.Ser1187Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. 4/4 in silico tools predict a benign outcome for this variant (SNPsandGO not captured due to low reliability index) with one in-silico predictive study on the protein function predicting this variant to be deleterious (Pavlicek_HMG_2004). The variant of interest has been found in a large, broad control population, ExAC in 3/120606 control chromosomes at a frequency of 0.0000249, which does not exceed the estimated maximal expected allele frequency of a pathogenic BRCA1 variant (0.0010005). This variant was reported in breast cancer patients without strong evidence for causality (Miller-Samuel_BRCA_SO_2011, Lee_BRCA2_BCR_2008, Schenkel_BRCA1&2_JMD_2016). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. Taken together, this variant is classified as VUS, until more definitive clinical and functional data become available.
Color Diagnostics, LLC DBA Color Health	RCV000217356	SCV000911108	likely benign	Hereditary cancer-predisposing syndrome	2016-08-06	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000586582	SCV001133557	uncertain significance	not provided	2023-08-14	criteria provided, single submitter	clinical testing	In the published literature, this variant has been reported in individuals/families with breast cancer (PMID: 30287823 (2018), 21810505 (2011), 18284688 (2008)). This variant has also been reported in an elderly cancer free individual (PMID: 32658311 (2011)). In addition, this variant is located in a region of the BRCA1 gene that is tolerant to missense sequence changes (PMID: 31911673 (2020)). The frequency of this variant in the general population, 0.000087 (3/34524 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.
University of Washington Department of Laboratory Medicine, University of Washington	RCV000217356	SCV003850149	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).
Breast Cancer Information Core (BIC) (BRCA1)	RCV000112118	SCV000144790	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2003-12-23	no assertion criteria provided	clinical testing