ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.1712T>C (p.Ile571Thr) (rs80357159)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 11
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000047565 SCV000075578 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 571 of the BRCA1 protein (p.Ile571Thr). The isoleucine residue is weakly conserved and there is a moderate physicochemical difference between isoleucine and threonine. This variant is present in population databases (rs80357159, ExAC 0.02%). This variant has been reported in individuals with breast and/or ovarian cancer (PMID: 20104584, 15726418, 21520273), as well as an individual with prostate cancer (PMID: 22516946). This variant has also been observed in an individual with breast, ovarian, and renal cell carcinoma (Invitae). However, in that individual a pathogenic allele was also identified in BRCA2, which suggests that this c.1712T>C variant was not the primary cause of disease. ClinVar contains an entry for this variant (Variation ID: 54330). 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. 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.
Ambry Genetics RCV000129336 SCV000184099 likely benign Hereditary cancer-predisposing syndrome 2018-04-06 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Other strong data supporting benign classification,In silico models in agreement (benign)
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000679683 SCV000224985 uncertain significance not provided 2014-10-02 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000173829 SCV000296392 uncertain significance not specified 2017-03-22 criteria provided, single submitter clinical testing
GeneDx RCV000679683 SCV000565817 uncertain significance not provided 2016-03-29 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.1712T>C at the cDNA level, p.Ile571Thr (I571T) at the protein level, and results in the change of an Isoleucine to a Threonine (ATA>ACA). This variant, also published as 1831T>C using alternate nomenclature, has been observed in several individuals with a history of breast cancer, as well as in at least one individual with prostate cancer (McKean-Cowdin 2005, Borg 2010, Leongamornlert 2012). BRCA1 Ile571Thr was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting 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 Ile571Thr occurs at a position that is not conserved across species and is located within the DNA binding domain and the region of interaction with STAT1 (Ouchi 2000, Narod 2004). In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available information, it is unclear whether BRCA1 Ile571Thr is pathogenic or benign. We consider it to be a variant of uncertain significance.
Counsyl RCV000111668 SCV000785433 uncertain significance Breast-ovarian cancer, familial 1 2017-08-08 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000679683 SCV000806900 uncertain significance not provided 2017-12-01 criteria provided, single submitter clinical testing
Mendelics RCV000047565 SCV000839280 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-07-02 criteria provided, single submitter clinical testing
Color RCV000129336 SCV000903115 likely benign Hereditary cancer-predisposing syndrome 2015-01-13 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000173829 SCV000918676 uncertain significance not specified 2018-03-07 criteria provided, single submitter clinical testing Variant summary: BRCA1 c.1712T>C (p.Ile571Thr) 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 1.2e-05 in 245748 control chromosomes (gnomAD and literature). This frequency is not significantly higher than expected for a pathogenic variant in BRCA1 causing Hereditary Breast and Ovarian Cancer (1.2e-05 vs 1.00e-03), allowing no conclusion about variant significance. c.1712T>C has been reported in the literature in affected individuals (Borg_2010, Leongamornlert_BRCA1_2012). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (1 VUS, 1 Likely benign). Based on the evidence outlined above, the variant was classified as uncertain significance.
Breast Cancer Information Core (BIC) (BRCA1) RCV000111668 SCV000144162 uncertain significance Breast-ovarian cancer, familial 1 1997-11-14 no assertion criteria provided clinical testing

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.