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
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.
Ambry Genetics RCV000132420 SCV000187512 likely benign Hereditary cancer-predisposing syndrome 2018-12-24 criteria provided, single submitter clinical testing Co-occurence with mutation in same gene (phase unknown);Other data supporting benign classification
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000586810 SCV000296484 uncertain significance not provided 2019-03-08 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
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.
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000484416 SCV000591494 uncertain significance not specified 2016-07-18 criteria provided, single submitter clinical testing
Color RCV000132420 SCV000683152 uncertain significance Hereditary cancer-predisposing syndrome 2018-05-24 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000484416 SCV000699110 uncertain significance not specified 2019-01-14 criteria provided, single submitter clinical testing Variant summary: BRCA1 c.4127C>G (p.Thr1376Arg) 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 2.2e-05 in 274930 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.4127C>G has been reported in the literature in individuals affected with cancer (Lu_2015, Judkins_2005). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. Co-occurrences with other pathogenic variant(s) have been reported (BRCA2 c.3296C>G, p.Ser1099X), providing supporting evidence for a benign role. A publication, Lu_2015, found the variant to not impede homology-directed repair or protein expression. Seven ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant predominantly as uncertain significance and once as likely benign. Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
Sharing Clinical Reports Project (SCRP) RCV000031152 SCV000053752 likely benign Breast-ovarian cancer, familial 1 2010-09-15 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000031152 SCV000144991 uncertain significance Breast-ovarian cancer, familial 1 2003-12-23 no assertion criteria provided clinical testing

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