ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.4934G>C (p.Arg1645Thr) (rs70953661)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000131365 SCV000186341 likely benign Hereditary cancer-predisposing syndrome 2018-03-08 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: In silico models in agreement (benign),Other data supporting benign classification
Invitae RCV000589552 SCV000254991 likely benign not provided 2019-03-05 criteria provided, single submitter clinical testing
GeneDx RCV000589552 SCV000321436 uncertain significance not provided 2018-10-16 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.4934G>C at the cDNA level, p.Arg1645Thr (R1645T) at the protein level, and results in the change of an Arginine to a Threonine (AGG>ACG). Using alternate nomenclature, this variant would be defined as BRCA1 5053G>C. In vitro-based functional assays showed this variant to have transcriptional activity comparable to wildtype (Woods 2016). BRCA1 Arg1645Thr was not observed at a significant allele frequency in large population cohorts (Lek 2016). BRCA1 Arg1645Thr is located in the BRCT1 domain and a region of interaction with multiple proteins (Paul 2014, UniProt). In-silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether BRCA1 Arg1645Thr is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Counsyl RCV000410761 SCV000488451 uncertain significance Breast-ovarian cancer, familial 1 2016-04-06 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000255486 SCV000591547 likely benign not specified 2012-11-05 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000589552 SCV000699183 uncertain significance not provided 2016-12-19 criteria provided, single submitter clinical testing Variant summary: The BRCA1 c.4934G>C (p.Arg1645Thr) variant involves the alteration of a non-conserved nucleotide. 3/4 in silico tools predict a benign outcome for this variant (SNPs&GO not captured due to low reliability index). This variant was found in 3/121410 control chromosomes at a frequency of 0.0000247, which does not exceed the estimated maximal expected allele frequency of a pathogenic BRCA1 variant (0.0010005). The variant has not been reported in affected individuals in the literature, but functional studies have shown the variant to have similar transcriptional acitivty compared to wild-type. While one clinical lab has classified the variant as likely benign, two others have classified it as a VUS via ClinVar. Because of the absence of clinical information, the variant is classified as a variant of uncertain significance (VUS) until additional information becomes available.
Color RCV000131365 SCV000911214 likely benign Hereditary cancer-predisposing syndrome 2016-04-25 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000589552 SCV001133598 likely benign not provided 2019-07-23 criteria provided, single submitter clinical testing
Mendelics RCV000410761 SCV001140504 uncertain significance Breast-ovarian cancer, familial 1 2019-05-28 criteria provided, single submitter clinical testing

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