ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.2123C>T (p.Ser708Phe) (rs80357182)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000131616 SCV000186633 likely benign Hereditary cancer-predisposing syndrome 2018-08-24 criteria provided, single submitter clinical testing Other strong data supporting benign classification;In silico models in agreement (benign)
Invitae RCV000205141 SCV000260784 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-03-06 criteria provided, single submitter clinical testing This sequence change replaces serine with phenylalanine at codon 708 of the BRCA1 protein (p.Ser708Phe). The serine residue is weakly conserved and there is a large physicochemical difference between serine and phenylalanine. 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: 91576). 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 phenylalanine 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. 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.
Counsyl RCV000077093 SCV000488697 uncertain significance Breast-ovarian cancer, familial 1 2016-05-27 criteria provided, single submitter clinical testing
GeneDx RCV000767161 SCV000566357 uncertain significance not provided 2018-09-14 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.2123C>T at the cDNA level, p.Ser708Phe (S708F) at the protein level, and results in the change of a Serine to a Phenylalanine (TCT>TTT). Using alternate nomenclature, this variant would be defined as BRCA1 2242C>T. This variant has not, to our knowledge, been published in the literature as a pathogenic or benign germline variant. BRCA1 Ser708Phe was not observed in large population cohorts (Lek 2016). This variant is located in the DNA binding domain and a region known to interact with multiple other proteins (Narod 2004, Paul 2014). 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 Ser708Phe is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000478406 SCV000600275 uncertain significance not specified 2017-02-18 criteria provided, single submitter clinical testing
Color RCV000131616 SCV000909352 likely benign Hereditary cancer-predisposing syndrome 2017-08-14 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000077093 SCV000108890 uncertain significance Breast-ovarian cancer, familial 1 2012-03-02 no assertion criteria provided clinical testing

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