ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.716A>T (p.His239Leu) (rs80357396)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000215014 SCV000275267 uncertain significance Hereditary cancer-predisposing syndrome 2016-02-26 criteria provided, single submitter clinical testing
Invitae RCV000226910 SCV000289840 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-08-24 criteria provided, single submitter clinical testing This sequence change replaces histidine with leucine at codon 239 of the BRCA1 protein (p.His239Leu). The histidine residue is moderately conserved and there is a moderate physicochemical difference between histidine and leucine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in an individual affected with breast cancer (PMID: 25186627). ClinVar contains an entry for this variant (Variation ID: 231422). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The leucine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.
Counsyl RCV000410574 SCV000489421 uncertain significance Breast-ovarian cancer, familial 1 2016-10-03 criteria provided, single submitter clinical testing
GeneDx RCV000485971 SCV000567570 uncertain significance not provided 2017-12-12 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.716A>T at the cDNA level, p.His239Leu (H239L) at the protein level, and results in the change of a Histidine to a Leucine (CAT>CTT). Using alternate nomenclature, this variant would be defined as BRCA1 835A>T. This variant has been reported in at least one individual with breast cancer (Tung 2015). BRCA1 His239Leu was not observed in large population cohorts (Lek 2016). Since Histidine and Leucine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA1 His239Leu is located in a region known to interact with multiple proteins (Paul 2014). In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Based on currently available evidence, it is unclear whether BRCA1 His239Leu is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Color RCV000215014 SCV000688660 uncertain significance Hereditary cancer-predisposing syndrome 2018-10-30 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000485971 SCV001133644 uncertain significance not provided 2019-02-13 criteria provided, single submitter clinical testing

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