ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.923G>C (p.Ser308Thr) (rs561998108)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000159947 SCV000210094 uncertain significance not provided 2017-06-30 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.923G>C at the cDNA level, p.Ser308Thr (S308T) at the protein level, and results in the change of a Serine to a Threonine (AGC>ACC). Using alternate nomenclature, this variant would be defined as BRCA1 1042G>C. Although this particular variant has not, to our knowledge, been published in the literature as pathogenic or benign, this site has been studied extensively. BRCA1 Ser308 was shown by Ouchi (2004) to be normally phosphorylated during the cell cycle, and a variant at that codon, BRCA1 Ser308Asn, abolished phosphorylation at this site. BRCA1 Ser308Thr was not observed at a significant allele frequency in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Serine and Threonine share similar properties, this is considered a conservative amino acid substitution. BRCA1 Ser308Thr occurs at a position where amino acids with properties similar to Serine are tolerated across species and is located at a known site of phosphorylation by Aurora-A kinase and in a region known to interact with multiple other proteins (Ouchi 2004, Paul 2014). 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 Ser308Thr is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000166933 SCV000217752 uncertain significance Hereditary cancer-predisposing syndrome 2017-02-06 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Invitae RCV000637409 SCV000758865 uncertain significance Hereditary breast and ovarian cancer syndrome 2017-12-28 criteria provided, single submitter clinical testing This sequence change replaces serine with threonine at codon 308 of the BRCA1 protein (p.Ser308Thr). The serine residue is moderately conserved and there is a small physicochemical difference between serine and threonine. This variant is present in population databases (rs561998108, ExAC 0.01%). This variant has not been reported in the literature in individuals with BRCA1-related disease. ClinVar contains an entry for this variant (Variation ID: 182129). 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: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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.

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