rs397508006
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000059.4(BRCA2):c.8754+1G>A variant causes a splice donor, intron change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Consequence
NM_000059.4 splice_donor, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| BRCA2 | ENST00000380152.8 | c.8754+1G>A | splice_donor_variant, intron_variant | Intron 21 of 26 | 5 | NM_000059.4 | ENSP00000369497.3 | |||
| BRCA2 | ENST00000530893.7 | c.8385+1G>A | splice_donor_variant, intron_variant | Intron 21 of 26 | 1 | ENSP00000499438.2 | ||||
| BRCA2 | ENST00000614259.2 | n.*812+1G>A | splice_donor_variant, intron_variant | Intron 20 of 25 | 2 | ENSP00000506251.1 |
Frequencies
GnomAD3 genomes
GnomAD4 exome Cov.: 32
GnomAD4 genome
ClinVar
Submissions by phenotype
Hereditary breast ovarian cancer syndrome Pathogenic:3
Variant summary: BRCA2 c.8754+1G>A 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: Four predict the variant abolishes a 5 splicing donor site. Exon trapping and RT-PCR analysis of patient blood showed that the mutation activates a cryptic splice site 46 base pairs 3' of exon 21, resulting in the inclusion of a premature stop codon and synthesis of a truncated BRCA2 protein (Hansen_2008). The variant was absent in 245740 control chromosomes (gnomAD). The variant, c.8754+1G>A, has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer, and in one case was reported as a de novo mutation (Francies_2015, Hansen_2008, Solano_2016, Thomassen_2008). These data indicate that the variant is likely to be associated with disease. Three 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. Based on the evidence outlined above, the variant was classified as pathogenic. -
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Studies have shown that disruption of this splice site results in insertion of intronic sequence and introduces a premature termination codon (PMID: 18597679). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 52667). Disruption of this splice site has been observed in individual(s) with breast and/or ovarian cancer (PMID: 18597679, 23199084, 28947987). In at least one individual the variant was observed to be de novo. It is commonly reported in individuals of Austrian ancestry (PMID: 23199084). This variant is not present in population databases (gnomAD no frequency). This sequence change affects a donor splice site in intron 21 of the BRCA2 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or disrupted protein product. -
Breast-ovarian cancer, familial, susceptibility to, 2 Pathogenic:2
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Hereditary cancer-predisposing syndrome Pathogenic:2
This variant causes a G to A nucleotide substitution at the +1 position of intron 21 of the BRCA2 gene. This variant is also known as IVS21+1G>A based on Breast Cancer Information Core (BIC) nomenclature. An RNA study has shown that this variant results in the use of a cryptic splice site in intron 21, and is expected to create a premature stop codon and result in an absent or non-functional protein product (PMID: 18597679). This variant has been reported in individuals affected with breast and ovarian cancer, and described as de novo in an individual affected with early onset breast cancer (PMID: 18597679, 28947987; Color internal data). This variant has been identified in one family among the CIMBA participants (PMID: 29446198) (https://cimba.ccge.medschl.cam.ac.uk/). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of BRCA2 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. -
The c.8754+1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide after coding exon 20 of the BRCA2 gene. This alteration was identified in a Danish patient diagnosed with breast cancer at 40. Functional analysis and RNA studies indicated abolishment of the native donor site and activation of a cryptic splice site 46 base pairs downstream in coding intron 20, resulting in a premature stop codon and truncated protein (Ambry internal data; Hansen TV et al. BMC Med. Genet. 2008;9:58). This alteration is reported to be an Austrian founder mutation (Janaviius R EPMA J 2010 Sep;1(3):397-412), but has also been identified in individuals from other countries (Solano AR et al. Oncotarget 2017 Sep;8(36):60487-60495). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition to the clinical data presented in the literature, 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. -
not provided Pathogenic:1
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Malignant tumor of breast Pathogenic:1
The BRCA2 c.8754+1G>A was first identified as a de novo mutation in a Danish breast cancer patient, and through minigene splicing assays was found to produce a transcript containing an additional 46 bp from intron 21 (confirmed by whole blood RNA based RT-PCR/sequencing), that resulted in a truncated BRCA2 protein (Hansen 2008). The variant was also later identified in 1 of 1880 proband chromosomes (frequency: 0.001) from Argentinian individuals or families with familial and/or personal history of breast/ovarian cancer (Solano 2016). The variant was also identified in dbSNP (ID: rs397508006) as “With Pathogenic allele”, Clinvitae database (classification pathogenic), and ARUP Laboratories BRCA Mutations Database (classification definitely pathogenic), the ClinVar database (classification pathogenic by Quest Diagnostics Nichols Institute San Juan Capistrano and the Consortium of Investigators of Modifiers of BRCA1/2 c/o University of Cambridge, and by Invitae (classification not provided)); it was not identified in GeneInsight COGR database, UMD, Fanconi Anemia Mutation Database (LOVD), LOVD-IARC database, COSMIC, 1000 Genomes Project, NHLBI GO Exome Sequencing Project, and the Exome Aggregation Consortium database (August 8, 2016). The c.8754+1G>A variant is predicted to cause abnormal splicing because the nucleotide substitution occurs in the invariant region of the splice consensus sequence. 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, correlating with the above published findings. In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at