ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.5406+5G>T (rs80358073)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 8
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000160008 SCV000210219 likely pathogenic not provided 2016-04-04 criteria provided, single submitter clinical testing This variant is denoted BRCA1 IVS21+5G>T or c.5406+5G>T and consists of a G>T nucleotide substitution at the +5 position of intron 21 of the BRCA1 gene. Multiple in silico models predict this variant to result in either a decrease or complete loss of the natural splice donor site, likely leading to abnormal gene splicing. This variant, also known as IVS22+5G>T or c.5525+5G>T using alternate nomenclature, has been reported in at least one woman with a history of breast cancer (Olopade 2003). While functional studies have not been performed on this variant, an RT-PCR study of a different variant at the same nucleotide position, BRCA1 c.5406+5G>A, demonstrated exon skipping leading a frameshift and premature termination (Petrij-Bosch 1997). BRCA1 c.5406+5G>T was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. The guanine (G) nucleotide that is altered is conserved across species. We consider this variant to be likely pathogenic.
Invitae RCV000476190 SCV000549369 likely pathogenic Hereditary breast and ovarian cancer syndrome 2020-05-04 criteria provided, single submitter clinical testing This sequence change falls in intron 21 of the BRCA1 gene. It does not directly change the encoded amino acid sequence of the BRCA1 protein, but it affects a nucleotide within the consensus splice site of the intron. This variant is not present in population databases (rs80358073, ExAC no frequency). This variant has been observed in several individuals affected with breast cancer (PMID: 12491487, 26681312). This variant is also known as IVS22+5G>T in the literature. ClinVar contains an entry for this variant (Variation ID: 37667). Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Experimental studies have shown that this variant disrupts BRCA1 mRNA splicing and/or protein function (PMID: 30209399). Experimental studies have shown that two different variants affecting this nucleotide (c.5406+5G>A and c.5406+5G>C) affect mRNA splicing, resulting in skipping of exon 22 of the BRCA1 mRNA (PMID: 9354803, 22505045). In addition, these variants have been observed in individuals and families affected with breast and/or ovarian cancer (PMID: 24010542, 26083025, 14985394, 9354803, 10090482), indicating that this nucleotide may be crucial for normal RNA splicing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Ambry Genetics RCV000562618 SCV000661028 likely pathogenic Hereditary cancer-predisposing syndrome 2016-11-16 criteria provided, single submitter clinical testing The c.5406+5G>T intronic variant results from a G to T substitution 5 nucleotides after coding exon 20 in the BRCA1 gene. This alteration, designated as IVS22+5G>T, was identified in an African American woman with breast cancer (Olopade OI et al. Cancer, 2003 Jan;97:236-45). A different nucleotide change at the same position, IVS22+5G>C or c.5406+5G>C, was reported in two unrelated individuals with triple negative breast cancer at ages 38 and 31 and in 1 of 473 Greek breast/ovarian cancer patients with a positive family history (Fostira F et al. Breast Cancer Res. Treat., 2012 Jul;134:353-62; Konstantopoulou I et al, Clin. Genet. 2014 Jan; 85(1):36-42). While functional studies have not been performed on this particular variant, two different nucleotide changes at the same position, IVS22+5G>A or c.5406+5G>A and c.5406+5G>C, were shown to result in the skipping of exon 22 (Petrij-Bosch A et al. Nat. Genet., 1997 Nov;17:341-5; Houdayer C et al Hum. Mutat. 2012 Aug; 33(8):1228-38). This variant was previously reported in the SNPDatabase as rs80358073, but was absent from population-based cohorts in the NHLBI Exome Sequencing Project (ESP) and 1000 Genomes Project databases. This nucleotide position is highly conserved in available vertebrate species. Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to weaken the efficiency of the native splice donor site, while it is predicted to abolish the native donor site using MaxEnt scan splice prediction tool; however, direct evidence is unavailable. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000780995 SCV000918739 uncertain significance not specified 2018-05-04 criteria provided, single submitter clinical testing Variant summary: BRCA1 c.5406+5G>T 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: two predict the variant abolishes a 5 splicing donor site and three predict the variant weakens a 5' donor site. However, these predictions have yet to be confirmed by functional studies. At least one study has shown that one different variant affecting this nucleotide (c.5406+5G>C) affects mRNA splicing, resulting in skipping of exon 22 (Houdayer_2012) and has been observed in individuals and families affected with breast and/or ovarian cancer (PMID: 24010542, 26083025, 14985394, 9354803, 10090482) supporting the conserved nature of this nucleotide position. The variant was absent in 277096 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. The variant, c.5406+5G>T, has been reported in the literature in one affected individual with a clinical history of breast cancer (Susswein_2016). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact of this specific variant on protein function and/or alternate splicing has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as likely pathogenic (2x) and VUS (1x). Based on the evidence outlined above, the variant was classified as uncertain significance until additional evidence pertaining to its co-segregation with breast/ovarian cancer in multiple independent individuals/families and a proven effect on nucleotide specific alternative splicing is obtained.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000160008 SCV001470399 likely pathogenic not provided 2019-11-22 criteria provided, single submitter clinical testing Not found in the total gnomAD dataset, and the data is high quality. Found in at least one patient with expected phenotype for this gene. Predicted to negatively affect a known splice site. Nucleotide conservation is uninformative. Assessment of experimental evidence suggests this variant results in abnormal protein function.
Sharing Clinical Reports Project (SCRP) RCV000031248 SCV000053852 pathogenic Breast-ovarian cancer, familial 1 2011-06-20 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000031248 SCV000145493 uncertain significance Breast-ovarian cancer, familial 1 2002-05-29 no assertion criteria provided clinical testing
Brotman Baty Institute,University of Washington RCV000031248 SCV001238310 not provided Breast-ovarian cancer, familial 1 no assertion provided in vitro

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.