ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.5277+1del (rs273901754)

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Total submissions: 12
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000164914 SCV000215602 pathogenic Hereditary cancer-predisposing syndrome 2017-11-29 criteria provided, single submitter clinical testing The c.5277+1delG intronic pathogenic mutation, located downstream of coding exon 18 in the BRCA1 gene, results from a deletion of one nucleotide at position c.5277+1. This nucleotide position is highly conserved in available vertebrate species. Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to abolish the native splice donor site and create a new cryptic donor site; however, direct evidence is unavailable. 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.
GeneDx RCV000236858 SCV000293939 pathogenic not provided 2016-02-11 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.5277+1delG or IVS19+1delG and consists of a deletion of one nucleotide at the +1 position of intron 19 of the BRCA1 gene. Using alternate nomenclature, this variant would be defined as BRCA1 5396+1delG or IVS20+1delG. The normal sequence, with the base that is deleted in braces, is AAAG[g]taaa, where the capital letters are exonic and lowercase are intronic. This 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. Although this variant has not, to our knowledge, been reported in the literature, BRCA1 c.5277+1G>A, occurring at the same position, has been reported in individuals with familial breast and/or ovarian cancer (de la Hoya 2001), and has been shown to lead to exon skipping by functional assays (Tesoriero 2005, Steffensen 2014). BRCA1 c.5277+1delG 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. Based on the current evidence, we consider this variant to be pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000077161 SCV000296447 pathogenic Breast-ovarian cancer, familial 1 2016-04-07 criteria provided, single submitter clinical testing
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000077161 SCV000326233 pathogenic Breast-ovarian cancer, familial 1 2015-10-02 criteria provided, single submitter clinical testing
Invitae RCV000457827 SCV000549380 pathogenic Hereditary breast and ovarian cancer syndrome 2020-03-28 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 19 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). Disruption of this splice site has been observed in individual(s) with breast and/or ovarian cancer (PMID: 30720863, 29446198, 11802208, 11149413, 11802209). ClinVar contains an entry for this variant (Variation ID: 91644). Experimental studies have shown that variants at canonical positions of this splice site disrupt mRNA splicing (PMID: 30209399). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000457827 SCV000699224 likely pathogenic Hereditary breast and ovarian cancer syndrome 2019-11-01 criteria provided, single submitter clinical testing Variant summary: BRCA1 c.5277+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: Three predict the variant weakens a 5' donor site. Two predict the variant abolishes a 5' splicing donor site. One predicts the variant abolishes a 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 251494 control chromosomes (gnomAD). c.5277+1delG has been reported in the literature in individuals affected with cancer or undergoing genetic testing (Judkins_2005, Heidemann_2012, LaDuca_2014, Rebbeck_2018). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six other ClinVar submitters (evaluation after 2014) cite the variant as pathogenic (n=5) or likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as likely pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000236858 SCV000887716 pathogenic not provided 2016-04-07 criteria provided, single submitter clinical testing
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology RCV000077161 SCV000993550 pathogenic Breast-ovarian cancer, familial 1 2019-07-22 criteria provided, single submitter research
Color Health, Inc RCV000164914 SCV001733556 likely pathogenic Hereditary cancer-predisposing syndrome 2020-07-21 criteria provided, single submitter clinical testing This variant causes a deletion of G nucleotide at the border of exon 19 and intron 19 splice donor site of the BRCA1 gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. Although functional studies have not been reported for this variant, this variant is expected to result in a disrupted protein product. This variant has been reported in an individual affected with ovarian and colorectal cancer (PMID: 22535016) and in individuals who underwent genetic testing (PMID: 16267036, 28152038, 29446198). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of BRCA1 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Likely Pathogenic.
Research and Development, ARUP Laboratories RCV001664261 SCV001879119 pathogenic Breast-ovarian cancer, familial 2; Breast-ovarian cancer, familial 1; Hereditary breast and ovarian cancer syndrome 2018-04-01 criteria provided, single submitter curation
Sharing Clinical Reports Project (SCRP) RCV000077161 SCV000108958 pathogenic Breast-ovarian cancer, familial 1 2010-11-16 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000077161 SCV000145424 pathogenic Breast-ovarian cancer, familial 1 2003-12-23 no assertion criteria provided clinical testing

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