ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.5306A>G (p.Tyr1769Cys) (rs397509257)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000048917 SCV000076930 uncertain significance Hereditary breast and ovarian cancer syndrome 2019-12-19 criteria provided, single submitter clinical testing This sequence change replaces tyrosine with cysteine at codon 1769 of the BRCA1 protein (p.Tyr1769Cys). The tyrosine residue is moderately conserved and there is a large physicochemical difference between tyrosine and cysteine. This variant is present in population databases (rs397509257, ExAC 0.05%). This variant has been reported in individuals affected with breast and/or ovarian cancer, as wells as in healthy control individuals (PMID: 22752604, 21965345, 29470806). ClinVar contains an entry for this variant (Variation ID: 55513). This variant has been reported to have conflicting or insufficient data to determine the effect on BRCA1 protein function (PMID: 30209399). 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 RCV000166677 SCV000217485 uncertain significance Hereditary cancer-predisposing syndrome 2019-09-12 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Counsyl RCV000409270 SCV000488527 uncertain significance Breast-ovarian cancer, familial 1 2016-04-20 criteria provided, single submitter clinical testing
GeneDx RCV000657045 SCV000567504 uncertain significance not provided 2018-01-11 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.5306A>G at the cDNA level, p.Tyr1769Cys (Y1769C) at the protein level, and results in the change of a Tyrosine to a Cysteine (TAT>TGT). Using alternate nomenclature, this variant would be defined as BRCA1 5425A>G. BRCA1 Tyr1769Cys was observed in an individual with ovarian cancer as well as in 1/50 women with sporadic breast cancer and 1/50 healthy controls in a study of BRCA1/2 mutations in women of Indian ethnicity (Akbari 2011, Juwle 2012). This variant was also identified in 1/50 healthy Central Asian individuals undergoing whole genome sequencing (Bodian 2014). Of note, the participants in this study were younger than 50 years old thus the unaffected status of this individual may not be significant. BRCA1 Tyr1769Cys was observed at an allele frequency of 0.05% (16/30,770) in individuals of South Asian ancestry in large population cohorts (Lek 2016). This variant is located in the second BRCT domain and a region known to interact with multiple other proteins (Paul 2014, UniProt). In silico analyses, which includes protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function. Based on currently available information, it is unclear whether BRCA1 Tyr1769Cys is pathogenic or benign. We consider it to be a variant of uncertain significance.
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000120264 SCV000591609 uncertain significance not specified 2015-05-19 criteria provided, single submitter clinical testing
Color RCV000166677 SCV000910943 likely benign Hereditary cancer-predisposing syndrome 2016-08-29 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000657045 SCV001133623 uncertain significance not provided 2019-01-11 criteria provided, single submitter clinical testing
Breast Center,Key Laboratory of Carcinogenesis and Translational Research RCV000048917 SCV001430324 uncertain significance Hereditary breast and ovarian cancer syndrome 2020-05-01 criteria provided, single submitter clinical testing
ITMI RCV000120264 SCV000084416 not provided not specified 2013-09-19 no assertion provided reference population
Brotman Baty Institute,University of Washington RCV000409270 SCV001238498 not provided Breast-ovarian cancer, familial 1 no assertion provided in vitro

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