ClinVar Miner

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

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Total submissions: 14
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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 2019-12-22 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 2021-03-15 criteria provided, single submitter clinical testing Observed in individuals with hereditary breast/ovarian cancer (Judkins 2005, Konecny 2011, Rebbeck 2018); Published functional studies demonstrate a damaging effect: classified as non-functional based on a saturation genome editing (SGE) assay measuring cell growth (Findlay 2018); Not observed in large population cohorts (Lek 2016); In silico analysis supports a deleterious effect on splicing; Also known as 5105+4A>T; This variant is associated with the following publications: (PMID: 29446198, 21203900, 23239986, 23348723, 30209399, 16267036)
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 2020-10-08 criteria provided, single submitter clinical testing The c.4986+4A>T intronic variant results from an A to T substitution 4 nucleotides after coding exon 14 in the BRCA1 gene. This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. Although direct splicing evidence is unavailable for this alteration, a close match alteration, c.4986+4A>G, shows retention of 65 nucleotides of the following intron leading to a frameshift and predicted premature termination codon (Wappenschmidt B et al. PLoS ONE, 2012 Dec;7:e50800). This same work and others show the same aberrant transcript results from other nucleotide substitutions at this splice site from the c.4986+1 through the c.4986+6 positions (Scholl T et al. Am. J. Med. Genet., 1999 Jul;85:113-6; Chen X et al. Hum. Mutat., 2006 May;27:427-35; Vreeswijk MP et al. Hum. Mutat., 2009 Jan;30:107-14; Wappenschmidt B et al. PLoS ONE, 2012 Dec;7:e50800; Colombo M et al. PLoS ONE, 2013 Feb;8:e57173). These alterations have also been observed in breast and ovarian cancer cohorts and some have been observed to segregate with disease in these families (Konecny M et al. Breast Cancer Res. Treat., 2011 Feb;126:119-30; Rebbeck TR et al, Hum Mutat, 2018 05;39:593-620; Ambry internal data). In addition, this variant, as well as the variants described as close matches were found non-functional in a high throughput genome editing haploid cell survival assay (Findlay GM et al. Nature, 2018 10;562:217-222). Based on the majority of available evidence to date, this variant is likely to be pathogenic.
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).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000048722 SCV000699189 pathogenic Hereditary breast and ovarian cancer syndrome 2021-08-30 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 249776 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. Eight 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/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Color Health, Inc 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.
Research and Development, ARUP Laboratories RCV001663971 SCV001877425 pathogenic Breast-ovarian cancer, familial 2; Breast-ovarian cancer, familial 1; Hereditary breast and ovarian cancer syndrome 2021-05-01 criteria provided, single submitter curation
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
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000255877 SCV001549574 likely pathogenic not provided no assertion criteria provided clinical testing The BRCA1 c.4986+4A>T variant was identified in 9 of 112430 proband chromosomes (frequency: 0.0001) from individuals or families with breast or ovarian cancer (Judkins 2005, Konecny 2011). The variant was also identified in dbSNP (ID: rs80358087) as "With Likely pathogenic, Pathogenic allele", in ClinVar (classified as likely benign by GeneDx, Counsyl, Ambry Genetics, Invitae, GeneKor MSA; as pathogenic by CIMBA, Integrated Genetics/Laboratory Corporation of America, SCRP, BIC), LOVD 3.0 (4x conflicting interpretations of pathogeny), BIC Database (3x with clinical importance), and ARUP Laboratories (class 5 - definitely pathogenic), databases. The variant was not identified in GeneInsight-COGR, UMD-LSDB, or in the Zhejiang University Database. The variant was not identified in the following control databases: the 1000 Genomes Project, the NHLBI GO Exome Sequencing Project, or the Genome Aggregation Database (Feb 27, 2017). The c.4986+4A>T variant is located in the 5' splice region but does not affect the invariant +1 and +2 positions. However, positions +3 to +6 are part of the splicing consensus sequence and variants involving these positions sometimes affect splicing. In addition, 5 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing. Several studies identified different nucleotides change at the same nucleotide position (c.4986+4A>G and c.4986+4A>C) (Wappenschmidt 2012, Meisel 2014). The c.4986+4A>G alteration create an aberrant transcript, which incorporates 65 intronic sequences following exon 16, and creates a stop codon at 1676 (p.Met1663ValfsX14) (Wappenschmidt 2012), which may be crucial for normal RNA splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more pathogenic role for this variant. This variant is classified as likely pathogenic.

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