ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.827C>G (p.Thr276Arg) (rs80357436)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000049161 SCV000077174 likely benign Hereditary breast and ovarian cancer syndrome 2017-09-20 criteria provided, single submitter clinical testing
Ambry Genetics RCV000165030 SCV000215727 uncertain significance Hereditary cancer-predisposing syndrome 2017-11-06 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
GeneDx RCV000766539 SCV000293065 uncertain significance not provided 2017-01-31 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.827C>G at the cDNA level, p.Thr276Arg (T276R) at the protein level, and results in the change of a Threonine to an Arginine (ACA>AGA). Using alternate nomenclature, this variant would be defined BRCA1 946C>G. This variant was observed in several breast and/or ovarian cancer patients (Judkins 2005, Lee 2008, Akbari 2011). BRCA1 Thr276Arg 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 Arginine differ in some properties, this is considered a semi-conservative amino acid substitution. BRCA1 Thr276Arg occurs at a position that is conserved in mammals and is located in the region of interaction with multiple proteins (Paul 2014). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available information, it is unclear whether BRCA1 Thr276Arg is pathogenic or benign. We consider it to be a variant of uncertain significance.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000236270 SCV000538454 uncertain significance not specified 2016-06-23 criteria provided, single submitter clinical testing Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Reported in 1 proband; ClinVar: 3 VUS
Color RCV000165030 SCV000903255 likely benign Hereditary cancer-predisposing syndrome 2016-03-07 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000236270 SCV000916809 uncertain significance not specified 2018-10-12 criteria provided, single submitter clinical testing Variant summary: BRCA1 c.827C>G (p.Thr276Arg) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.3e-05 in 276556 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.827C>G has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer without strong evidence for or against causality. Thus, these reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. At least one publication reports experimental evidence evaluating an impact on protein function, however, does not allow convincing conclusions about the variant effect (Starita_2015). Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Based on the evidence outlined above, the variant was classified as uncertain significance.
Sharing Clinical Reports Project (SCRP) RCV000031287 SCV000053892 benign Breast-ovarian cancer, familial 1 2011-10-04 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000031287 SCV000145696 uncertain significance Breast-ovarian cancer, familial 1 2002-05-29 no assertion criteria provided clinical testing
Research Molecular Genetics Laboratory,Women's College Hospital, University of Toronto RCV000236270 SCV000587079 uncertain significance not specified 2014-01-31 no assertion criteria provided research

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