ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.2897T>C (p.Ile966Thr) (rs879254045)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000759511 SCV000293275 uncertain significance not provided 2015-10-20 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.2897T>C at the cDNA level, p.Ile966Thr (I966T) at the protein level, and results in the change of an Isoleucine to a Threonine (ATT>ACT). Using alternate nomenclature, this variant would be defined as BRCA1 3016T>C. This variant has not, to our knowledge, been published in the literature as being pathogenic or benign. BRCA1 Ile966Thr was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Isoleucine and Threonine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA1 Ile966Thr occurs at a position that is not conserved and is located in the DNA binding domain and a region known to interact with multiple other proteins (Narod 2004, Paul 2014). In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available evidence, it is unclear whether BRCA1 Ile966Thr is pathogenic or benign.
Ambry Genetics RCV000566390 SCV000665828 uncertain significance Hereditary cancer-predisposing syndrome 2018-01-30 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000759511 SCV000888876 uncertain significance not provided 2018-07-13 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000779905 SCV000916810 uncertain significance not specified 2018-10-12 criteria provided, single submitter clinical testing Variant summary: BRCA1 c.2897T>C (p.Ile966Thr) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 121300 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.2897T>C in individuals affected with Hereditary Breast and Ovarian Cancer and no experimental evidence demonstrating its impact on protein function have been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and both classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Invitae RCV000792554 SCV000931858 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-12-14 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with threonine at codon 966 of the BRCA1 protein (p.Ile966Thr). The isoleucine residue is weakly conserved and there is a moderate physicochemical difference between isoleucine and threonine. 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 conditions. ClinVar contains an entry for this variant (Variation ID: 246006). 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 threonine 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.

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