ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.5522G>A (p.Ser1841Asn) (rs80357368)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000236784 SCV000292708 uncertain significance not provided 2016-01-19 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.5522G>A at the cDNA level, p.Ser1841Asn (S1841N) at the protein level, and results in the change of a Serine to an Asparagine (AGT>AAT). Using alternate nomenclature, this variant would be defined as BRCA1 5641G>A. One set of in vitro functional assays interrogating this variant's impact on protein stability, peptide binding and specificity, and transcriptional activity suggests a pathogenic effect (Lee 2010). However, in vivo assays have found uncertain results. Growth assays by Quaresima et al. (2006) revealed that cells expressing BRCA1 Ser1841Asn were capable of forming comparable numbers of cell colonies as wild-type, but the Ser1841Asn colonies were reported to be smaller in size. Likewise, this study also found that cells expressing BRCA1 Ser1841Asn demonstrated reduced, but not absent, p53 binding (Quaresima 2006). BRCA1 Ser1841Asn 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. This variant occurs at a position that is conserved across species and is located in the BRCT 2 domain as well as a region known to interact with multiple proteins (Narod 2004, Paul 2014). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on the currently available evidence, we consider BRCA1 Ser1841Asn to be a variant of uncertain significance.
Color Health, Inc RCV000583863 SCV000688640 uncertain significance Hereditary cancer-predisposing syndrome 2019-02-11 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000236784 SCV001133640 uncertain significance not provided 2018-11-09 criteria provided, single submitter clinical testing
Breast Center,Key Laboratory of Carcinogenesis and Translational Research RCV001254337 SCV001430322 pathogenic Hereditary breast and ovarian cancer syndrome 2020-05-01 criteria provided, single submitter clinical testing
Invitae RCV001254337 SCV001536377 uncertain significance Hereditary breast and ovarian cancer syndrome 2020-10-19 criteria provided, single submitter clinical testing This sequence change replaces serine with asparagine at codon 1841 of the BRCA1 protein (p.Ser1841Asn). The serine residue is highly conserved and there is a small physicochemical difference between serine and asparagine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with breast cancer and/or ovarian cancer (PMID: 28364669, 29752822). ClinVar contains an entry for this variant (Variation ID: 55613). Experimental studies have shown that this variant affects BRCA1 protein function (PMID: 30765603, 28781887, 30209399, 16786532, 20378548, 16969499, 17005433, 25748678, 30257991). 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.
Breast Cancer Information Core (BIC) (BRCA1) RCV000112694 SCV000145566 uncertain significance Breast-ovarian cancer, familial 1 2000-06-12 no assertion criteria provided clinical testing
Brotman Baty Institute,University of Washington RCV000112694 SCV001244053 not provided Breast-ovarian cancer, familial 1 no assertion provided in vitro

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