ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.4127C>G (p.Thr1376Arg) (rs80356986)

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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 RCV000132420 SCV000187512 likely benign Hereditary cancer-predisposing syndrome 2017-09-14 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Co-occurence with mutation in same gene (phase unknown),Other data supporting benign classification
Breast Cancer Information Core (BIC) (BRCA1) RCV000031152 SCV000144991 uncertain significance Breast-ovarian cancer, familial 1 2003-12-23 no assertion criteria provided clinical testing
Color RCV000132420 SCV000683152 uncertain significance Hereditary cancer-predisposing syndrome 2018-05-24 criteria provided, single submitter clinical testing
Counsyl RCV000031152 SCV000488586 uncertain significance Breast-ovarian cancer, familial 1 2016-05-03 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000484416 SCV000591494 uncertain significance not specified 2016-07-18 criteria provided, single submitter clinical testing
GeneDx RCV000586810 SCV000567750 uncertain significance not provided 2019-01-17 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.4127C>G at the cDNA level, p.Thr1376Arg (T1376R) 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 as BRCA1 4246C>G. This variant has been reported in a cohort of individuals who had undergone clinical BRCA1 analysis (Judkins 2005), and one functional study found this variant to retain homology-directed repair activity (Lu 2015). BRCA1 Thr1376Arg was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the SCD domain and a region known to interact with multiple other proteins (Narod 2004, Paul 2014). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether BRCA1 Thr1376Arg is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000586810 SCV000699110 uncertain significance not provided 2017-05-26 criteria provided, single submitter clinical testing Variant summary: The BRCA1 c.4127C>G (p.Thr1376Arg) variant involves the alteration of a conserved nucleotide, resulting in a missense substitution that is not located within a known functional domain (InterPro). 2/3 in silico tools predict a damaging outcome for this variant (SNPsandGO and Mutation Taster not captured due to low reliability index and low p-value, respectively). This variant was found in the large control database ExAC at a frequency of 0.0000196 (2/102020 control chromosomes), which does not exceed the estimated maximal expected allele frequency of a pathogenic BRCA1 variant (0.0010005). The variant has been identified in patients reported in the literature without strong support for pathogenicity (Judkins_Can Res_2005; Lu_BRCA_Nature Comms_2015). Homology-directed repair (HDR) assays showed the variant does not affect HDR activity, though appropriate controls were not available for evaluation (Lu_BRCA_Nature Comms_2015). Multiple clinical diagnostic laboratories/reputable databases have classified this variant with conflicting interpretations, including uncertain significance (5x in ClinVar) and likely benign (2x in ClinVar). Taken together, this variant is classified as a VUS until additional information becomes available.
Invitae RCV000048453 SCV000076466 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-09-06 criteria provided, single submitter clinical testing This sequence change replaces threonine with arginine at codon 1376 of the BRCA1 protein (p.Thr1376Arg). The threonine residue is moderately conserved and there is a moderate physicochemical difference between threonine and arginine. This variant is present in population databases (rs80356986, ExAC 0.004%). This variant has not been reported in the literature in individuals with BRCA1-related disease. ClinVar contains an entry for this variant (Variation ID: 37571). An experimental study has shown that this missense change does not impact the protein expression or homology-directed repair activity of the BRCA1 protein (PMID: 26689913). 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.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000484416 SCV000296484 uncertain significance not specified 2017-02-20 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000031152 SCV000053752 likely benign Breast-ovarian cancer, familial 1 2010-09-15 no assertion criteria provided clinical testing

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