ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.1258G>T (p.Asp420Tyr) (rs80357488)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000047396 SCV000075409 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-11-12 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with tyrosine at codon 420 of the BRCA1 protein (p.Asp420Tyr). The aspartic acid residue is highly conserved and there is a large physicochemical difference between aspartic acid and tyrosine. This variant is not present in population databases (rs80357488, ExAC no frequency). This variant has been observed in an individual with a personal and/or family history of breast and/or ovarian cancer (PMID: 29161300). This variant has also been reported in individuals in the Breast Cancer Information Core database (PMID: 10923033). However, in one individual, a pathogenic allele was identified in the BRCA1 gene, which suggests that this c.1258G>T substitution in BRCA1 was not the primary cause of disease in that individual. ClinVar contains an entry for this variant (Variation ID: 54178). 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: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C15"). However, based on a multifactorial likelihood algorithm using genetic, statistical and in silico data, this variant has been determined to have a low probability of being pathogenic (PMID: 21990134, 17924331). 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.
GeneDx RCV000212163 SCV000209922 likely benign not specified 2015-05-30 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Ambry Genetics RCV000222994 SCV000276775 likely benign Hereditary cancer-predisposing syndrome 2015-06-23 criteria provided, single submitter clinical testing
Color RCV000222994 SCV000688324 likely benign Hereditary cancer-predisposing syndrome 2017-07-21 criteria provided, single submitter clinical testing
Mendelics RCV000047396 SCV000839290 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-07-02 criteria provided, single submitter clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000111575 SCV000144042 uncertain significance Breast-ovarian cancer, familial 1 2004-02-20 no assertion criteria provided clinical testing

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