Submissions for variant NM_007294.4(BRCA1):c.5193+1del

dbSNP: rs397509236

Total submissions: 10

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, susceptibility to, 1	2015-10-02	criteria provided, single submitter	clinical testing
GeneDx	RCV000486777	SCV000566620	pathogenic	not provided	2023-07-18	criteria provided, single submitter	clinical testing	Canonical splice site variant emonstrated to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease (Wappenschmidt et al., 2012); Observed in individuals with a personal and family history consistent with pathogenic variants in this gene (Wappenschmidt et al., 2012; Heidemann et al., 2012); Not observed at significant frequency in large population cohorts (gnomAD); Also known as 5312+1del; This variant is associated with the following publications: (PMID: 23239986, 29446198, 22535016)
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, susceptibility to, 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 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
Labcorp Genetics (formerly Invitae), Labcorp	RCV001264597	SCV001584616	pathogenic	Hereditary breast ovarian cancer syndrome	2023-06-30	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Studies have shown that this premature translational stop signal results in deletion of the last nucleotide of exon 18 due to the activation of a cryptic splice site and introduces a premature termination codon (PMID: 23239986; Invitae). The resulting mRNA is expected to undergo nonsense-mediated decay. ClinVar contains an entry for this variant (Variation ID: 55449). This variant is also known as c.5193+1del, IVS19+1delG. This premature translational stop signal has been observed in individual(s) with breast and ovarian cancer (PMID: 22535016, 23239986). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (Splice site) in the BRCA1 gene. RNA analysis indicates that this premature translational stop signal induces altered splicing and may result in an absent or disrupted protein product.
Ambry Genetics	RCV002336196	SCV002643229	pathogenic	Hereditary cancer-predisposing syndrome	2021-02-08	criteria provided, single submitter	clinical testing	The c.5193+1delG intronic pathogenic mutation, located in intron 17 of the BRCA1 gene, results from a deletion of one nucleotide within intron 17 of the BRCA1 gene. This alteration has been reported in conjunction with a BRCA2 mutation an individual with both ovarian cancer and coecum cancer at age 61 years (Heidemann S et al. Breast Cancer Res. Treat. 2012 Aug;134(3):1229-39). This alteration was also identified in a large, worldwide study of BRCA1/2 mutation positive families (Rebbeck TR et al. Hum Mutat, 2018 05;39:593-620). In silico splice site analysis predicts that this alteration will weaken the native splice donor site and will result in the creation or strengthening of a novel splice donor site. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data; Wappenschmidt B et al. PLoS ONE 2012 Dec;7(12):e50800). In addition to the clinical data presented in the literature, alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as a disease-causing mutation.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000486777	SCV002774309	pathogenic	not provided	2021-06-27	criteria provided, single submitter	clinical testing	This variant is located in a canonical splice-donor site and interferes with normal BRCA1 mRNA splicing. Additionally, in vitro splicing analysis shows that the variant results in a frameshift (PMID: 23239986 (2012)). Based on the available information, this variant is classified as pathogenic.
German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne	RCV000785210	SCV000923778	pathogenic	Ovarian neoplasm	2018-12-01	no assertion criteria provided	research