ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.8754+4A>G (rs81002893)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) RCV000077450 SCV001161712 pathogenic Breast-ovarian cancer, familial 2 2019-06-18 reviewed by expert panel curation Allele-specific assay on patient-derived mRNA demonstrated that the variant allele produces only predicted non-functional transcripts. Variant allele produces r.8754_8755ins8754+1_8754+46 transcript (PMID: 22505045). A mRNA splicing mini-gene assay has concordant results (PMID: 25382762).
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000077450 SCV000296634 pathogenic Breast-ovarian cancer, familial 2 2015-11-18 criteria provided, single submitter clinical testing
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000077450 SCV000327956 pathogenic Breast-ovarian cancer, familial 2 2015-10-02 criteria provided, single submitter clinical testing
Counsyl RCV000077450 SCV000489073 likely pathogenic Breast-ovarian cancer, familial 2 2016-08-19 criteria provided, single submitter clinical testing
Ambry Genetics RCV000565525 SCV000665078 pathogenic Hereditary cancer-predisposing syndrome 2019-02-16 criteria provided, single submitter clinical testing The c.8754+4A>G intronic pathogenic mutation results from an A to G substitution 4 nucleotides after coding exon 20 in the BRCA2 gene. The effect of this splicing alteration has been investigated using an mRNA based assay, and was shown to result in loss of the native donor site and the subsequent activation of a cryptic splice site at position c.IVS21+46 resulting in a 46-bp insertion (due to intron retention), creating a premature stop codon at position c.IVS21+9 (Bonatti F et al, Cancer Genet. Cytogenet. 2006 Oct; 170(2):93-101). A minigene assay found that the c.8754+4A>G mutation produced 100% aberrant transcript IVS21-ins46 and was classified as pathogenic by authors (Acedo A et al, Hum. Mutat. 2015 Feb; 36(2):210-21). This alteration has also been classified as likely pathogenic by multifactorial analyses, which integrates multiple lines of evidence to produce a quantitative likelihood of pathogenicity (Easton DF et al. Am. J. Hum. Genet. 2007 Nov;81:873-83; Lindor NM et al. Hum. Mutat. 2012 Jan;33:8-21; Vallee MP et al. Hum. Mutat. 2012 Jan;33:22-8; Parsons MT et al. Hum. Mutat., 2019 09;40:1557-1578). Of note, this alteration is also designated as IVS21+4A>G in published literature. Based on the available evidence, c.8754+4A>G is classified as a pathogenic mutation.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000501422 SCV000695178 pathogenic Hereditary breast and ovarian cancer syndrome 2016-04-07 criteria provided, single submitter clinical testing Variant Summary: The variant of interest is located at a conserved intronic position, in which 5/5 splicing prediction programs via Alamut predict a loss (or weakening) effect on a canonical RNA splicing donor site. The variant of interest was not observed in controls (ExAC, 1000 Gs, ESP), but has been reported in multiple affected individuals via publications. Multiple independent functional studies show that this variant can cause a loss of intron 21 donor site, which leads to consequent activation of a cryptic splice site at position IVS21+46. The resulting transcript retained a 46-bp fragment of intron 21 and generates a stop codon at position c.IVS21+9, resulting in a truncated protein and consequently, suggesting a deleterious effect of this variant (Bontti_2006, Acedo_2014, and Houdayer_2012). In addition, multiple clinical laboratories/databases cite the variant with a classification of "Pathogenic/Causal." Therefore, taking all available lines of evidence into consideration, the variant of interest is classified as Pathogenic.
Color Health, Inc RCV000565525 SCV000904694 pathogenic Hereditary cancer-predisposing syndrome 2015-03-05 criteria provided, single submitter clinical testing
Invitae RCV000501422 SCV001577939 pathogenic Hereditary breast and ovarian cancer syndrome 2020-09-02 criteria provided, single submitter clinical testing This sequence change falls in intron 21 of the BRCA2 gene. It does not directly change the encoded amino acid sequence of the BRCA2 protein, but it affects a nucleotide within the consensus splice site of the intron. This variant is not present in population databases (rs81002893, ExAC no frequency). This variant has been reported in an individual affected with ovarian cancer (PMID: 17011978), an individual affected with prostate cancer (PMID: 27433846), and in an individual affected with male breast cancer (PMID: 20927582). This variant is also known as IVS21+4A>G in the literature. ClinVar contains an entry for this variant (Variation ID: 52669) Based on multifactorial likelihood algorithms using genetic, in silico, and statistical data, this variant has been determined to have a high probability of being pathogenic (PMID: 17924331, 21990134). Furthermore, experimental studies have shown that this variant causes a loss of the intron 21 splice donor site and activation of a cryptic splice site 46 bp downstream of the consensus site. This generates a stop codon in intron 21 and subsequent truncation of the BRCA2 protein (PMID: 17011978, 22505045, 25382762). For these reasons, this variant has been classified as Pathogenic.
Sharing Clinical Reports Project (SCRP) RCV000077450 SCV000109248 pathogenic Breast-ovarian cancer, familial 2 2012-05-01 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000077450 SCV000147448 uncertain significance Breast-ovarian cancer, familial 2 2004-02-20 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001353977 SCV000592225 pathogenic Malignant tumor of breast no assertion criteria provided clinical testing The BRCA2 c.8754+4A>G variant was identified by Houdayer (2012) in an individual referred for BRCA1/2 analysis based on personal or family history. The variant was also identified in dbSNP (ID: rs81002893) “With other allele”, HGMD as “disease causing mutation”, LOVD, COSMIC, ClinVar database, the BIC database (7X with unknown clinical importance), and UMD (2X as a causal variant). The variant was classified as a pathogenic variant by the Sharing Clinical Reports Project (SCRP) (submitted within the ClinVar database and derived from Myriad reports). The c.8754+4A>G 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. Five in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing, and two studies using mRNA analysis demonstrated abnormal splicing with a loss of the intron 21 donor site and consequent activation of a cryptic splice site downstream (Bonatti 2006, Houdayer 2012). In addition, two multifactorial probability-based models classified the variant as likely causal or pathogenic (Easton 2007, Lindor 2012). In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic.

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