ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.2750T>C (p.Ile917Thr)

gnomAD frequency: 0.00001  dbSNP: rs587781492
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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 RCV000129456 SCV000184226 uncertain significance Hereditary cancer-predisposing syndrome 2021-09-16 criteria provided, single submitter clinical testing The p.I917T variant (also known as c.2750T>C), located in coding exon 9 of the BRCA1 gene, results from a T to C substitution at nucleotide position 2750. The isoleucine at codon 917 is replaced by threonine, an amino acid with similar properties. This amino acid position is not 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 RCV000697286 SCV000825886 uncertain significance Hereditary breast ovarian cancer syndrome 2022-06-21 criteria provided, single submitter clinical testing This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 917 of the BRCA1 protein (p.Ile917Thr). This variant is present in population databases (rs587781492, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with BRCA1-related conditions. ClinVar contains an entry for this variant (Variation ID: 141097). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt BRCA1 protein function. 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 RCV000759509 SCV000888870 uncertain significance not provided 2017-12-15 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001175509 SCV001339114 uncertain significance not specified 2020-03-23 criteria provided, single submitter clinical testing Variant summary: BRCA1 c.2750T>C (p.Ile917Thr) 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 allele was found at a frequency of 4e-06 in 250846 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.2750T>C in individuals affected with Hereditary Breast and Ovarian Cancer and no experimental evidence demonstrating its impact on protein function have been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Color Diagnostics, LLC DBA Color Health RCV000129456 SCV001359694 uncertain significance Hereditary cancer-predisposing syndrome 2021-04-07 criteria provided, single submitter clinical testing This missense variant replaces isoleucine with threonine at codon 917 of the BRCA1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in a breast cancer case-control study in one individual each in the affected and unaffected groups (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA1_006389). This variant has been identified in 2/282236 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
University of Washington Department of Laboratory Medicine, University of Washington RCV000129456 SCV003849373 likely benign Hereditary cancer-predisposing syndrome 2023-03-23 criteria provided, single submitter curation Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673).
GeneDx RCV000759509 SCV004025617 uncertain significance not provided 2023-08-08 criteria provided, single submitter clinical testing Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; Also known as 2869T>C; This variant is associated with the following publications: (PMID: 15343273)

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