ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.230C>T (p.Thr77Met) (rs80357209)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000216581 SCV000276530 uncertain significance Hereditary cancer-predisposing syndrome 2015-06-26 criteria provided, single submitter clinical testing
GeneDx RCV000587004 SCV000572470 uncertain significance not provided 2018-10-24 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.230C>T at the cDNA level, p.Thr77Met (T77M) at the protein level, and results in the change of a Threonine to a Methionine (ACG>ATG). Using alternate nomenclature, this variant would be defined as BRCA1 349C>T. This variant was observed in at least one individual with breast cancer and in an individual with thyroid cancer (Fackenthal 2012, Yehia 2018). Upon functional interrogation, BRCA1 Thr77Met performed similarly to wildtype in homology directed-repair and saturation genome editing assays (Findlay 2018, Starita 2018). In another study, this variant was found to retain BARD1 binding, while decreasing E2 binding and abolishing E3 ligase activity (Morris 2006). BRCA1 Thr77Met was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the RING domain and in 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 Thr77Met is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000587004 SCV000698938 uncertain significance not provided 2017-05-22 criteria provided, single submitter clinical testing Variant summary: The BRCA1 c.230C>T (p.Thr77Met) variant involves the alteration of a conserved nucleotide, resulting in a missense substitution that lies within the Zinc finger, RING/FYVE/PHD-type domain (InterPro). 3/3 in silico tools predict a damaging outcome for this variant (SNPs&GO and Mutation Taster not captured due to low reliability index and low probability score, respectively). This variant was found in the large control database ExAC at a frequency of 0.0000247 (3/121304 control chromosomes), which does not exceed the estimated maximal expected allele frequency of a pathogenic BRCA1 variant (0.0010005). In the literature, the variant has been cited in HBOC patients without strong evidence for pathogenicity (Fackenthal_IJC_2012; Judkins_Cancer Res_2005). Functional studies have shown that the variant does not impact exon 6 skipping or inclusion (Raponi_HM_2011), nor does it affect the interaction between BRCA1 and BARD1 (Morris_HMG_2006). However, the variant did disrupt the interaction with ubiquitination enzyme E2 and caused a lack of ubiquitination presumed to result from the loss of E3 ubiquitin ligase function of BRCA1, similar to a known disruptive mutation used as a negative control (Morris_HMG_2006). However, at-least one study has reported that tumor suppression by BRCA1 depends on BRCT phosphoprotein binding, but not its E3 ligase activity (Shakya_Science_2011) . Therefore, the results from the functional assays, may not be directly related to the molecular mechanism of disease in-vivo and awaits additional studies to confirm these findings. Multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. Taken together, this variant is classified as VUS until additional evidence is obtained.
Counsyl RCV000077514 SCV000785427 uncertain significance Breast-ovarian cancer, familial 1 2017-08-02 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000587004 SCV000888863 uncertain significance not provided 2018-04-25 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000077514 SCV000109314 uncertain significance Breast-ovarian cancer, familial 1 2012-09-20 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000077514 SCV000144745 uncertain significance Breast-ovarian cancer, familial 1 2002-05-29 no assertion criteria provided clinical testing

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