ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.2387C>T (p.Thr796Ile) (rs80357364)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000047818 SCV000075831 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-10-02 criteria provided, single submitter clinical testing This sequence change replaces threonine with isoleucine at codon 796 of the BRCA1 protein (p.Thr796Ile). The threonine residue is moderately conserved and there is a moderate physicochemical difference between threonine and isoleucine. This variant is present in population databases (rs80357364, ExAC 0.05%). This variant has been observed in individuals affected with breast or ovarian cancer (PMID: 27257965, 28664449, 27907908). ClinVar contains an entry for this variant (Variation ID: 54551). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; 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.
GeneDx RCV000588791 SCV000210130 uncertain significance not provided 2014-08-15 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.2387C>T at the cDNA level, p.Thr796Ile (T796I) at the protein level, and results in the change of a Threonine to an Isoleucine (ACA>ATA). This variant, also known as 2506C>T using alternate nomenclature, has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA1 Thr796Ile 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 Threonine and Isoleucine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA1 Thr796Ile occurs at a position that is moderately conserved across species and is not located in a known functional domain. In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available information, it is unclear whether BRCA1 Thr796Ile is pathogenic or benign. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000167276 SCV000218119 uncertain significance Hereditary cancer-predisposing syndrome 2017-06-16 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: In silico models in agreement (deleterious) and/or completely conserved position in appropriate species,Insufficient or conflicting evidence
Laboratory of Molecular Diagnosis of Cancer,West China Hospital, Sichuan University RCV000240714 SCV000265884 uncertain significance Neoplasm of the breast 2015-11-01 criteria provided, single submitter research
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000212168 SCV000600285 uncertain significance not specified 2017-04-04 criteria provided, single submitter clinical testing
Color RCV000167276 SCV000683030 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-24 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000588791 SCV000698945 uncertain significance not provided 2016-09-27 criteria provided, single submitter clinical testing Variant summary: The BRCA1 c.2387C>T (p.Thr796Ile) variant causes a missense change involving a non-conserved nucleotide with 3/4 in silico tools (SNPs&GO not captured due to low reliability index) predicting a "damaging" outcome, although these predictions have yet to be functionally assessed. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 4/121326 (1/30330), predominantly in the East Asian cohort, 4/8652 (1/2163), which does not exceed the estimated maximal expected allele frequency for a pathogenic BRCA1 variant of 1/1000. A publication has cited the variant in an affected individual with limited information (ie, lack of co-occurrence and cosegregation data). Multiple clinical diagnostic laboratories have cited the variant with a classification of "uncertain significance." Therefore, taking all available lines of evidence into consideration, the variant of interest has been classified as a VUS until additional information becomes available.
Breast Cancer Information Core (BIC) (BRCA1) RCV000111839 SCV000144399 uncertain significance Breast-ovarian cancer, familial 1 2002-05-29 no assertion criteria provided clinical testing

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