ClinVar Miner

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

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000048722 SCV000076735 likely pathogenic Hereditary breast and ovarian cancer syndrome 2018-09-07 criteria provided, single submitter clinical testing This variant affects a highly conserved nucleotide within the consensus splice site of intron 15 of the BRCA1 mRNA. The majority of introns (70-73%) have an adenine at this position (PMID: 9536098). This variant is present in population databases (rs80358087, ExAC 0.01%). This variant has been reported in two families affected with breast and/or ovarian cancer (PMID: 21203900). It has also been observed in several individuals with early-onset breast cancer (Invitae). ClinVar contains an entry for this variant (Variation ID: 55342). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. Different variants affecting this nucleotide (c.4986+4A>G and c.4986+4A>C) have been observed in individuals with breast or ovarian cancer (PMID: 23239986, 25281711), and c.4986+4A>G has been shown experimentally to create an aberrant transcript by incorporating 65 intronic sequences immediately following exon 15, and results in a stop codon at residue 1676 (p.Met1663Valfs*14) (PMID: 23239986). This indicates 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.
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 2018-03-28 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: 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 2017-11-01 criteria provided, single submitter clinical testing
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 2018-06-06 criteria provided, single submitter clinical testing
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

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