ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.547+1G>C

dbSNP: rs80358030
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000545283 SCV000636044 pathogenic Hereditary breast ovarian cancer syndrome 2022-10-28 criteria provided, single submitter clinical testing ClinVar contains an entry for this variant (Variation ID: 462674). Disruption of this splice site has been observed in individual(s) with breast and/or ovarian cancer (PMID: 9333265, 23940062, 25556971). This variant is not present in population databases (gnomAD no frequency). This sequence change affects a donor splice site in intron 7 of the BRCA1 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or disrupted protein product. Studies have shown that disruption of this splice site alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 22505045, 23451180, 24667779). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000545283 SCV001362916 likely pathogenic Hereditary breast ovarian cancer syndrome 2019-11-21 criteria provided, single submitter clinical testing Variant summary: BRCA1 c.547+1G>C 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: Five 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 251436 control chromosomes (gnomAD). To our knowledge, no occurrence of c.547+1G>C in individuals affected with Hereditary Breast and Ovarian Cancer and no experimental evidence demonstrating its impact on protein function have been reported. A ClinVar submission (evaluation after 2014) cites the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.

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