ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.5467+1G>A (rs80358145)

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Total submissions: 12
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000049003 SCV000077016 pathogenic Hereditary breast and ovarian cancer syndrome 2019-12-27 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 22 of the BRCA1 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant has been reported in individuals affected with breast and ovarian cancer (PMID: 11428389, 21913181, 25428789, 19491284). ClinVar contains an entry for this variant (Variation ID: 37673). Experimental studies have shown that this sequence change results in skipping of exon 22 (also known as exon 23) (PMID: 11428389, 24667779). This variant is also known as IVS23+1G>A in the literature. 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.
Ambry Genetics RCV000162888 SCV000213375 pathogenic Hereditary cancer-predisposing syndrome 2018-04-23 criteria provided, single submitter clinical testing Functionally-validated splicing mutation;Alterations at the canonical donor/acceptor sites (+/- 1, 2) without other strong (b-level) evidence supporting pathogenicity
Counsyl RCV000031254 SCV000220766 likely pathogenic Breast-ovarian cancer, familial 1 2014-10-03 criteria provided, single submitter literature only
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000031254 SCV000296467 pathogenic Breast-ovarian cancer, familial 1 2016-05-11 criteria provided, single submitter clinical testing
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000031254 SCV000326319 pathogenic Breast-ovarian cancer, familial 1 2015-10-02 criteria provided, single submitter clinical testing
GeneDx RCV000430282 SCV000516012 pathogenic not provided 2017-06-13 criteria provided, single submitter clinical testing This pathogenic variant is denoted BRCA1 c.5467+1G>A or IVS22+1G>A and consists of a G>A nucleotide substitution at the +1 position of intron 22 of the BRCA1 gene. The variant destroys a canonical splice donor site and causes abnormal gene splicing, leading to either an abnormal message that is subject to nonsense-mediated mRNA decay or to an abnormal protein product. Splicing assays have demonstrated that this variant, also defined as BRCA1 5586+1G>A (IVS23+1G>A) using alternate nomenclature, results in skipping of exon 22 (previously reported as exon 23) (Laskie Ostrow 2001, Steffensen 2014). BRCA1 c.5467+1G>A has been observed in several individuals with breast cancer, including those with early-onset disease and/or a family history of breast or ovarian cancer (Litton 2012, Churpek 2015, Kang 2015, Lynce 2015, Pal 2015, Cao 2016, Park 2017). Based on currently available evidence, we consider this variant to be pathogenic.
Color RCV000162888 SCV000683319 pathogenic Hereditary cancer-predisposing syndrome 2015-01-21 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000430282 SCV000888948 pathogenic not provided 2016-05-11 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000049003 SCV000916825 pathogenic Hereditary breast and ovarian cancer syndrome 2018-12-18 criteria provided, single submitter clinical testing Variant summary: The variant, BRCA1 c.5467+1G>A 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. Two predict the variant creates a 5 donor site. Experimental evidence suggests that this variant affects mRNA splicing (Laskie_2001, Steffensen_2014). At least one publication reports experimental evidence evaluating an impact on protein function (Findlay_2018) and the variant effect resulted in <10% of normal activity. The variant was absent in 121404 control chromosomes (ExAC) and has been reported in the literature in multiple individuals affected with Hereditary Breast and Ovarian Cancer (Laskie_2001, Litton_2012, Judkins_2005, John_2007, Haffty_2009, Kang_2015, Mannan_2016, Chan_2018). These data indicate that the variant is very likely to be associated with disease. Six 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 pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Sharing Clinical Reports Project (SCRP) RCV000031254 SCV000053858 pathogenic Breast-ovarian cancer, familial 1 2011-01-06 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000031254 SCV000145521 pathogenic Breast-ovarian cancer, familial 1 2002-05-29 no assertion criteria provided clinical testing
Brotman Baty Institute,University of Washington RCV000031254 SCV001243929 not provided Breast-ovarian cancer, familial 1 no assertion provided in vitro

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