ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.2564A>C (p.Gln855Pro) (rs768001441)

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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 RCV000165754 SCV000216498 uncertain significance Hereditary cancer-predisposing syndrome 2015-10-02 criteria provided, single submitter clinical testing Insufficient or conflicting evidence;In silico models in agreement (deleterious) and/or completely conserved position in appropriate species
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000506725 SCV000600294 uncertain significance not specified 2017-01-07 criteria provided, single submitter clinical testing
Color RCV000165754 SCV000683047 uncertain significance Hereditary cancer-predisposing syndrome 2019-04-23 criteria provided, single submitter clinical testing
Invitae RCV000637567 SCV000759031 uncertain significance Hereditary breast and ovarian cancer syndrome 2019-12-13 criteria provided, single submitter clinical testing This sequence change replaces glutamine with proline at codon 855 of the BRCA1 protein (p.Gln855Pro). The glutamine residue is highly conserved and there is a moderate physicochemical difference between glutamine and proline. This variant is not present in population databases (ExAC no frequency). This variant has been reported in an individual affected with breast and/or ovarian cancer (PMID: 11802209, 30287823, 29176636). ClinVar contains an entry for this variant (Variation ID: 186203). 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: "Probably 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.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000758797 SCV000887644 uncertain significance not provided 2017-12-01 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000506725 SCV000918714 uncertain significance not specified 2018-03-05 criteria provided, single submitter clinical testing Variant summary: BRCA1 c.2564A>C (p.Gln855Pro) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 246196 control chromosomes (in gnomAD and publication data). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. The c.2564A>C variant has been reported in the literature in two individuals affected with Hereditary Breast and Ovarian Cancer (Meindl 2002, Nakamura 2013), however these reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. Co-occurrence with a pathogenic BRCA2 variant have been reported (the details of the co-occurring variant was not specified), providing supporting evidence for a benign role (Nakamura 2013). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

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