ClinVar Miner

Submissions for variant NM_032043.2(BRIP1):c.1474-1G>A (rs1555603638)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000569916 SCV000666198 likely pathogenic Hereditary cancer-predisposing syndrome 2016-08-29 criteria provided, single submitter clinical testing Alterations at the canonical donor/acceptor sites (+/- 1, 2) without other strong (b-level) evidence supporting pathogenicity;In silico models in agreement (deleterious) and/or completely conserved position in appropriate species
Counsyl RCV000662723 SCV000785483 likely pathogenic Fanconi anemia, complementation group J; Neoplasm of ovary 2017-08-18 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000758988 SCV000887981 likely pathogenic not provided 2018-03-06 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000780062 SCV000917084 likely pathogenic Familial cancer of breast 2018-09-07 criteria provided, single submitter clinical testing Variant summary: BRIP1 c.1474-1G>A is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Three predict the variant abolishes a 5' splicing donor site and also introduces a cryptic 5' donor site 1bp into the exon, which is predicted to lead to a frameshift and truncated or absent protein. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 246022 control chromosomes (gnomAD). To our knowledge, no occurrence of c.1474-1G>A in individuals affected with Hereditary Breast and Ovarian Cancer and no experimental evidence demonstrating its impact on protein function have been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and both classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.

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