ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.4986+4A>T (rs80358087)

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Total submissions: 12
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000048722 SCV000076735 pathogenic Hereditary breast and ovarian cancer syndrome 2019-12-23 criteria provided, single submitter clinical testing This sequence change falls in intron 15 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 present in population databases (rs80358087, ExAC 0.01%). This variant has been observed in several families affected with breast and/or ovarian cancer (PMID: 21203900). ClinVar contains an entry for this variant (Variation ID: 55342). 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 mRNA splicing and/or protein function (PMID: 30209399). Different variants affecting this nucleotide (c.4986+4A>G and c.4986+4A>C) have been determined to be pathogenic (PMID: 23239986, 25281711, 29446198, 30209399). This suggests that this nucleotide is important for normal RNA splicing, and that other variants at this position may also be pathogenic. For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV000255877 SCV000322159 likely pathogenic not provided 2018-01-23 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.4986+4A>T or IVS15+4A>T and consists of an A>T nucleotide substitution at the +4 position of intron 15 of the BRCA1 gene. Using alternate nomenclature, this variant would also be defined as 5105+4A>T. Multiple in silico models predict this variant to damage the nearby natural splice donor site, and to possibly cause abnormal gene splicing. This variant was observed in at least two families with hereditary breast/ovarian cancer (Konecny 2011). BRCA1 c.4986+4A>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 adenine (A) nucleotide that is altered is conserved across species. Based on the currently available information, we consider BRCA1 c.4986+4A>T to be a likely pathogenic variant.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000077590 SCV000326082 pathogenic Breast-ovarian cancer, familial 1 2015-10-02 criteria provided, single submitter clinical testing
Counsyl RCV000077590 SCV000488615 likely pathogenic Breast-ovarian cancer, familial 1 2016-05-11 criteria provided, single submitter clinical testing
Ambry Genetics RCV000509792 SCV000607772 likely pathogenic Hereditary cancer-predisposing syndrome 2018-10-08 criteria provided, single submitter clinical testing Well-characterized mutation at same position;Rarity in general population databases (dbsnp, esp, 1000 genomes);In silico models in agreement (deleterious) and/or completely conserved position in appropriate species
GeneKor MSA RCV000255877 SCV000693497 likely pathogenic not provided 2020-01-01 criteria provided, single submitter clinical testing This sequence change occurs 4 bases after exon 15 of the BRCA1 gene. This position is conserved in the human and other genomes and might be involved in mRNA processing. This variant is expected to result in incorrect splicing, alteration in the reading frame and an absent or truncated protein. This variant is also known as 5105+4A>T and has been described in the literature in at least two families with hereditary breast and ovarian cancer (PMID: 21203900). This sequence change is listed in population databases at very low frequency (rs80358087, <0.1%). The mutation database ClinVar contains entries for this variant (Variation ID: 55342).
Integrated Genetics/Laboratory Corporation of America RCV000048722 SCV000699189 pathogenic Hereditary breast and ovarian cancer syndrome 2019-01-30 criteria provided, single submitter clinical testing Variant summary: BRCA1 c.4986+4A>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: three predict the variant abolishes a 5' splicing donor site, while one predict the variant weakens a 5' donor site. An in vitro study that assessed the effect of the variant in a haploid human cell line whose survival is dependent on intact BRCA1 function, found that the variant resulted in loss of function (Findlay_2018). In addition, the variant is located in close proximity to other known pathogenic variants, such IVS16+3G>C, IVS16+4A>C, IVS16+6T>G, IVS16+6T>C that were proven to impair the splice donor site of intron 16 and showed incorporation of 65 nucleotide of the 5' end of intron 16 in all cases (Wappenschmidt_2012). The variant was absent in 244498 control chromosomes (gnomAD). c.4986+4A>T has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer (Konency_2011, Judkins_2005, Rebbeck_2018). These data indicate that the variant is likely to be associated with disease. Six ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as likely pathogenic/pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Color RCV000509792 SCV000903285 likely pathogenic Hereditary cancer-predisposing syndrome 2020-01-03 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000255877 SCV001133602 likely pathogenic not provided 2018-09-07 criteria provided, single submitter clinical testing Not found in the total gnomAD dataset, and the data is high quality (0/275154 chr). Found in at least one symptomatic patient. 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) RCV000077590 SCV000109393 pathogenic Breast-ovarian cancer, familial 1 2012-10-09 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000077590 SCV000145235 pathogenic Breast-ovarian cancer, familial 1 2002-05-29 no assertion criteria provided clinical testing
Brotman Baty Institute,University of Washington RCV000077590 SCV001243316 not provided Breast-ovarian cancer, familial 1 no assertion provided in vitro

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