ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.301+2dup (rs273899694)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000467483 SCV000549430 uncertain significance Hereditary breast and ovarian cancer syndrome 2019-11-27 criteria provided, single submitter clinical testing This sequence change falls in intron 5 of the BRCA1 mRNA. It does not directly change the encoded amino acid sequence of the BRCA1 protein. This variant is not present in population databases (rs273899694, ExAC no frequency) and has not been reported in the literature in individuals with a BRCA1-related disease. ClinVar contains an entry for this variant (Variation ID: 125664). Algorithms developed to predict the effect of nucleotide changes on mRNA splicing suggest that this intronic variant may alter mRNA splicing, but this prediction has not been confirmed by published transcriptional studies. In summary, this is a rare intronic change with uncertain impact on splicing. It has been classified as a Variant of Uncertain Significance.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000759514 SCV000888881 uncertain significance not provided 2018-05-17 criteria provided, single submitter clinical testing
Ambry Genetics RCV001018056 SCV001179235 uncertain significance Hereditary cancer-predisposing syndrome 2019-08-10 criteria provided, single submitter clinical testing The c.301+2dupT intronic variant results from a duplication of the T nucleotide located two nucleotides after coding exon 4 of the BRCA1 gene. This nucleotide position is highly conserved in available vertebrate species. Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to abolish the native splice donor site. Alterations at this donor site are known to produce an in frame transcript impacting four amino acids in the BRCA1 RING domain (Ambry internal data). One functional study found that nucleotide substitutions at this donor site are non-functional in a high-throughput, genome editing, haploid cell survival assay (Findlay GM et al. Nature, 2018 10;562:217-222). However this alteration has also been identified in trans with a pathogenic mutation in BRCA1 in an individual without features of Fanconi Anemia (Ambry internal data, personal communication). Since supporting evidence is conflicting at this time, the clinical significance of this alteration remains unclear.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001192523 SCV001360723 uncertain significance not specified 2019-09-23 criteria provided, single submitter clinical testing Variant summary: BRCA1 c.301+2dupT alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 251180 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.301+2dupT 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 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.
Breast Cancer Information Core (BIC) (BRCA1) RCV000112241 SCV000144956 pathogenic Breast-ovarian cancer, familial 1 2001-02-16 no assertion criteria provided clinical testing
Sharing Clinical Reports Project (SCRP) RCV000112241 SCV000297595 likely benign Breast-ovarian cancer, familial 1 2012-08-28 no assertion criteria provided clinical testing

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