ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.2666C>T (p.Ser889Phe) (rs769712441)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000166405 SCV000217199 uncertain significance Hereditary cancer-predisposing syndrome 2020-08-03 criteria provided, single submitter clinical testing The p.S889F variant (also known as c.2666C>T), located in coding exon 9 of the BRCA1 gene, results from a C to T substitution at nucleotide position 2666. The serine at codon 889 is replaced by phenylalanine, an amino acid with highly dissimilar properties. This alteration was identified in a cohort of pediatric patients referred for genetic testing for diverse clinical indications (Chirita-Emandi A et al. Sci Rep. 2020 01;10:223). In a study of whole-exome sequencing in patients with features of Cowden syndrome (CS) or Bannayan-Riley-Ruvalcaba syndrome (BRRS) and negative PTEN testing, this alteration was identified in 0/87 patients with CS or BRRS and 1/3476 patients from The Cancer Genome Atlas (TCGA) (Yehia L et al. PLoS Genet. 2018 04;14:e1007352). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae RCV000232849 SCV000289763 uncertain significance Hereditary breast and ovarian cancer syndrome 2020-06-10 criteria provided, single submitter clinical testing This sequence change replaces serine with phenylalanine at codon 889 of the BRCA1 protein (p.Ser889Phe). The serine residue is moderately conserved and there is a large physicochemical difference between serine and phenylalanine. This variant is present in population databases (rs769712441, ExAC no frequency). This variant has been reported in an individual with breast cancer (PMID: 21918853). This variant is also known as 2785C>T in the literature. ClinVar contains an entry for this variant (Variation ID: 186759). 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: Possibly 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.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000758802 SCV000887651 uncertain significance not provided 2019-11-11 criteria provided, single submitter clinical testing
Color Health, Inc RCV000166405 SCV000911272 likely benign Hereditary cancer-predisposing syndrome 2017-06-08 criteria provided, single submitter clinical testing
GeneDx RCV000758802 SCV001801418 uncertain significance not provided 2020-03-17 criteria provided, single submitter clinical testing Not observed at a significant frequency in large population cohorts (Lek 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with breast cancer (de Juan Jimenez 2012); Also known as 2785C>T; This variant is associated with the following publications: (PMID: 33206719, 31937788, 27767231, 21918853)

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