ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.5193+1del (rs397509236)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000258440 SCV000326197 pathogenic Breast-ovarian cancer, familial 1 2015-10-02 criteria provided, single submitter clinical testing
GeneDx RCV000486777 SCV000566620 pathogenic not provided 2015-05-16 criteria provided, single submitter clinical testing This pathogenic variant is denoted BRCA1 c.5193+1delG or IVS18+1delG and consists of a deletion of the guanine (G) nucleotide at the +1 position of intron 18 of the BRCA1 gene. The variant destroys a canonical splice donor site and is predicted to cause abnormal gene splicing, leading to either an abnormal message that is subject to nonsense-mediated mRNA decay or to an abnormal protein product. This variant has not, to our knowledge, been published in the literature. Based on the current evidence, we consider BRCA1 c.5193+1delG to be pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001001277 SCV001158452 pathogenic not specified 2019-05-02 criteria provided, single submitter clinical testing The BRCA1 c.5193+1delG variant (rs397509236), also known as IVS19+1delG, is reported in the literature in a family affected with breast and ovarian cancer, although a pathogenic BRCA2 variant was also reported in this family (Heidemann 2012). The c.5193+1delG variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism, and it is reported as pathogenic by several laboratories in ClinVar (Variation ID: 55449). This variant abolishes the canonical splice donor site of intron 19, which is likely to disrupt gene function. Based on available information, this variant is considered to be pathogenic. References: Heidemann S et al. Double heterozygosity for mutations in BRCA1 and BRCA2 in German breast cancer patients: implications on test strategies and clinical management. Breast Cancer Res Treat. 2012 Aug;134(3):1229-39.
Institute of Human Genetics, University of Leipzig Medical Center RCV000258440 SCV001440854 pathogenic Breast-ovarian cancer, familial 1 2019-01-01 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001264597 SCV001442829 pathogenic Hereditary breast and ovarian cancer syndrome 2020-10-22 criteria provided, single submitter clinical testing Variant summary: BRCA1 c.5193+1delG 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: Four predict the variant abolishes canonical 5 splicing donor site and three predict the variant creates a new 5 donor site. At least one publication reports experimental evidence that this variant affects mRNA splicing. Wappenschmidt et al report that the variant did not associate with a suspicious splicing pattern when performed gel electrophoresis of RT-PCR products. However, sequencing revealed the deletion of the last 3nucleotide of exon on mRNA level due to the activation of a cryptic splice site which includes the last nucleotide of that exon (Wappenschmidt_2012). The variant was absent in 251130 control chromosomes (gnomAD). c.5193+1delG has been reported in the literature in multiple individuals affected with Hereditary Breast and Ovarian Cancer Syndrome (example: Rebbeck_2018, Wappenschmidt_2012). These data indicate that the variant is very likely to be associated with disease. Four ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen RCV000486777 SCV001448111 likely pathogenic not provided 2020-10-23 criteria provided, single submitter clinical testing
Invitae RCV001264597 SCV001584616 pathogenic Hereditary breast and ovarian cancer syndrome 2020-06-15 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 18 of the BRCA1 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals affected with breast and ovarian cancer (PMID: 23239986, 22535016). This variant is also known as IVS19+1delG in the literature. ClinVar contains an entry for this variant (Variation ID: 55449). Experimental studies have shown that this sequence change disrupts normal RNA splicing (PMID: 23239986). Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in BRCA1 are known to be pathogenic (PMID: 20104584). For these reasons, this variant has been classified as Pathogenic.
German Consortium for Hereditary Breast and Ovarian Cancer Center Cologne,University Hospital Cologne RCV000785210 SCV000923778 pathogenic Neoplasm of ovary 2018-12-01 no assertion criteria provided research

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