ClinVar Miner

Submissions for variant NM_007294.3(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 2016-08-04 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
GeneDx RCV000586582 SCV000292976 uncertain significance not provided 2017-01-17 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.3560G>A at the cDNA level, p.Ser1187Asn (S1187N) at the protein level, and results in the change of a Serine to an Asparagine (AGC>AAC). This variant, also published as BRCA1 3679G>A using alternate nomenclature, has been reported in an individual with breast cancer and abdominal wall sarcoma as well as an individual with suspected Hereditary Breast and Ovarian Cancer (Miller-Samuel 2011, Schenkel 2016). BRCA1 Ser1187Asn was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Serine and Asparagine share similar properties, this is considered a conservative amino acid substitution. BRCA1 Ser1187Asn occurs at a position that is not conserved and is not located in a known functional domain (Narod 2004). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether BRCA1 Ser1187Asn is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America 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 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 2018-08-31 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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