ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.4934G>C (p.Arg1645Thr) (rs70953661)

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Total submissions: 10
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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 In silico models in agreement (benign);Other data supporting benign classification
Invitae RCV001081541 SCV000254991 likely benign Hereditary breast and ovarian cancer syndrome 2020-11-25 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
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000255486 SCV000699183 likely benign not specified 2020-12-18 criteria provided, single submitter clinical testing Variant summary: BRCA1 c.4934G>C (p.Arg1645Thr) results in a non-conservative amino acid change located in the BRCT domain (IPR001357) of 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 2e-05 in 251254 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.4934G>C in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome has been reported. A co-occurrence with a pathogenic variant has been reported by a ClinVar submitter (BRCA2 unspecified variant), providing supporting evidence for a benign role. Experimental evidence evaluating an impact on protein function through utilization of a cell-survival assay and transcriptional assays, demonstrated the variant to be functional/not pathogenic (e.g. Woods_2016, Findlay_2018, Fernandes_2019). Four ClinVar submitters (evaluation after 2014) cite the variant as likely benign and three ClinVar submitters (evaluation after 2014) cite it as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign.
Color Health, Inc 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
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001354024 SCV000591547 likely benign Malignant tumor of breast no assertion criteria provided clinical testing The p.Arg1645Thr variant has not been reported in the literature but has been listed in the Exome Variant Server database. The p.Arg1645 residue is not conserved in mammals, and the variant amino acid Threonine (Thr) is present in the opossum and chicken at this position, increasing the likelihood that an alteration to this residue may not have functional significance. Computational analyses (PolyPhen, SIFT, AlignGVGD) do not predict any effect on the protein function, however, this information is not predictive enough to assume pathogenicity. The variant is listed in the dbSNP database (ID#:rs70953661) as coming from a "clinical source" but no frequency information was provided, and so the prevalence of this variant in the population is not known. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as predicted benign.
Brotman Baty Institute,University of Washington RCV000410761 SCV001243235 not provided Breast-ovarian cancer, familial 1 no assertion provided in vitro

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