ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.2738A>G (p.Asn913Ser) (rs199954851)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000217466 SCV000276496 uncertain significance Hereditary cancer-predisposing syndrome 2018-12-20 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
GeneDx RCV000758804 SCV000568023 uncertain significance not provided 2018-11-30 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.2738A>G at the cDNA level, p.Asn913Ser (N913S) at the protein level, and results in the change of an Asparagine to a Serine (AAT>AGT). Using alternate nomenclature, this variant would be defined as BRCA1 2857A>G. This variant has not, to our knowledge, been published in the literature as a pathogenic or benign germline variant. BRCA1 Asn913Ser was not observed in large population cohorts (Lek 2016). This variant is located in the DNA binding domain and the RAD51 binding domain (Chen 1998, Narod 2004). In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether BRCA1 Asn913Ser is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000478791 SCV000600300 uncertain significance not specified 2016-09-30 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000758804 SCV000887654 uncertain significance not provided 2018-03-12 criteria provided, single submitter clinical testing
Invitae RCV000794318 SCV000933718 uncertain significance Hereditary breast and ovarian cancer syndrome 2019-05-02 criteria provided, single submitter clinical testing This sequence change replaces asparagine with serine at codon 913 of the BRCA1 protein (p.Asn913Ser). The asparagine residue is weakly conserved and there is a small physicochemical difference between asparagine and serine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with BRCA1-related disease. ClinVar contains an entry for this variant (Variation ID: 232370). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The serine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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.
Color RCV000217466 SCV001359695 uncertain significance Hereditary cancer-predisposing syndrome 2019-05-08 criteria provided, single submitter clinical testing

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