ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.4541C>T (p.Ser1514Phe) (rs863224761)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000198645 SCV000254988 uncertain significance Hereditary breast and ovarian cancer syndrome 2015-05-10 criteria provided, single submitter clinical testing This sequence change replaces serine with phenylalanine at codon 1514 of the BRCA1 protein (p.Ser1514Phe). The serine residue is moderately conserved and there is a large physicochemical difference between serine and phenylalanine. This variant has not been published in the literature and is not present in population databases. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). In summary, this is a novel missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance.
GeneDx RCV000478928 SCV000571624 uncertain significance not provided 2016-09-08 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.4541C>T at the cDNA level, p.Ser1514Phe (S1514F) 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 4660C>T. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA1 Ser1514Phe 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 Phenylalanine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA1 Ser1514Phe occurs at a position that is not conserved and is located in the SCD domain and a region known to interact with multiple other proteins (Chen 1998, Narod 2004, Clark 2012). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, it is unclear whether BRCA1 Ser1514Phe is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000564652 SCV000668438 uncertain significance Hereditary cancer-predisposing syndrome 2016-08-04 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Color RCV000564652 SCV000909019 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-25 criteria provided, single submitter clinical testing

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