ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.1367T>C (p.Ile456Thr) (rs80357360)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000047443 SCV000075456 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-07-10 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with threonine at codon 456 of the BRCA1 protein (p.Ile456Thr). The isoleucine residue is moderately conserved and there is a moderate physicochemical difference between isoleucine and threonine. This variant is present in population databases (rs80357360, ExAC 0.001%). This variant has been reported in individuals in the Breast Cancer Information Core database (PMID: 10923033). ClinVar contains an entry for this variant (Variation ID: 54222). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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 RCV000130503 SCV000185372 uncertain significance Hereditary cancer-predisposing syndrome 2017-10-12 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
GeneDx RCV000383569 SCV000329120 uncertain significance not provided 2018-10-24 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.1367T>C at the cDNA level, p.Ile456Thr (I456T) at the protein level, and results in the change of an Isoleucine to a Threonine (ATT>ACT). Using alternate nomenclature, this variant would be defined as BRCA1 1486T>C. This variant has been reported in at least one individual referred for BRCA1 testing (Judkins 2005). BRCA1 Ile456Thr was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the DNA binding 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 Ile456Thr is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Counsyl RCV000111597 SCV000786351 uncertain significance Breast-ovarian cancer, familial 1 2018-04-18 criteria provided, single submitter clinical testing
Color RCV000130503 SCV000911714 uncertain significance Hereditary cancer-predisposing syndrome 2018-10-30 criteria provided, single submitter clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000111597 SCV000144068 uncertain significance Breast-ovarian cancer, familial 1 2002-05-29 no assertion criteria provided clinical testing

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