ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.3560G>A (p.Ser1187Asn) (rs80356975)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000048233 SCV000076246 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-11-13 criteria provided, single submitter clinical testing This sequence change replaces serine with asparagine at codon 1187 of the BRCA1 protein (p.Ser1187Asn). The serine residue is moderately conserved and there is a small physicochemical difference between serine and asparagine. This variant is present in population databases (rs80356975, ExAC 0.02%). This variant has been reported in a patient affected with breast cancer and abdominal wall sarcoma (PMID: 21810505). This variant is also known as c.3679G>A in the literature. ClinVar contains an entry for this variant (Variation ID: 54917). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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 2020-08-11 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 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 Health, Inc 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 2020-03-06 criteria provided, single submitter clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000112118 SCV000144790 uncertain significance Breast-ovarian cancer, familial 1 2003-12-23 no assertion criteria provided clinical testing

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