13-32376795-A-T
Position:
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2PP5_Very_Strong
The NM_000059.4(BRCA2):c.8754+4A>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Genomes: not found (cov: 32)
Consequence
BRCA2
NM_000059.4 splice_region, intron
NM_000059.4 splice_region, intron
Scores
2
Splicing: ADA: 0.9880
1
1
Clinical Significance
Conservation
PhyloP100: 3.47
Genes affected
BRCA2 (HGNC:1101): (BRCA2 DNA repair associated) Inherited mutations in BRCA1 and this gene, BRCA2, confer increased lifetime risk of developing breast or ovarian cancer. Both BRCA1 and BRCA2 are involved in maintenance of genome stability, specifically the homologous recombination pathway for double-strand DNA repair. The largest exon in both genes is exon 11, which harbors the most important and frequent mutations in breast cancer patients. The BRCA2 gene was found on chromosome 13q12.3 in human. The BRCA2 protein contains several copies of a 70 aa motif called the BRC motif, and these motifs mediate binding to the RAD51 recombinase which functions in DNA repair. BRCA2 is considered a tumor suppressor gene, as tumors with BRCA2 mutations generally exhibit loss of heterozygosity (LOH) of the wild-type allele. [provided by RefSeq, May 2020]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 10 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 13-32376795-A-T is Pathogenic according to our data. Variant chr13-32376795-A-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 220353.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
BRCA2 | ENST00000380152.8 | c.8754+4A>T | splice_region_variant, intron_variant | 5 | NM_000059.4 | ENSP00000369497.3 | ||||
BRCA2 | ENST00000530893.7 | c.8385+4A>T | splice_region_variant, intron_variant | 1 | ENSP00000499438.2 | |||||
BRCA2 | ENST00000614259.2 | n.*812+4A>T | splice_region_variant, intron_variant | 2 | ENSP00000506251.1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
Cov.:
32
GnomAD4 exome Cov.: 32
GnomAD4 exome
Cov.:
32
GnomAD4 genome Cov.: 32
GnomAD4 genome
Cov.:
32
ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:5Uncertain:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Hereditary cancer-predisposing syndrome Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Nov 01, 2023 | This variant causes an A to T nucleotide substitution at the +4 position of intron 21 of the BRCA2 gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. RNA studies have shown this variant produces a mutant transcript that partially retains 46 nucleotides of intron 21, creating a frameshift and premature translation stop signal (PMID: 31642931, 32133419, 36446827). This variant has not been reported in individuals affected with BRCA2-related disorders in the literature. However, a different variant at the same nucleotide position, BRCA2 c.8754+4A>G, has been reported as Pathogenic (ClinVar variation ID 52669). The BRCA2 c.8754+4A>T 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 Likely Pathogenic. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 13, 2023 | The c.8754+4A>T intronic variant results from an A to T substitution 4 nucleotides after coding exon 20 in the BRCA2 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 and will result in the creation or strengthening of a novel splice donor site. RNA studies have demonstrated this alteration results in abnormal splicing (Ambry internal data). Another alteration impacting the same donor site (c.8754+4A>G) has been shown to have a similar impact on splicing and is predicted to be pathogenic in multifactorial analyses (Bonatti F et al. Cancer Genet Cytogenet 2006 Oct;170(2):93-101; Acedo A et al. Hum Mutat 2015 Feb;36(2):210-21; Lindor NM et al. Hum Mutat 2012 Jan;33(1):8-21.) . Based on the majority of available evidence to date, this variant is likely to be pathogenic. - |
Hereditary breast ovarian cancer syndrome Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Sep 02, 2022 | Variant summary: BRCA2 c.8754+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: One predict the variant abolishes the canonical 5' splicing donor site. Three predict the variant weakens the canonical 5' splicing donor site. At least two publications report experimental evidence that this variant affects mRNA splicing by activation of a downstream intronic splice donor leading to a retention of 46 nucleotides (example, Karam_2019, Landrith_2020). The variant was absent in 250906 control chromosomes. To our knowledge, no occurrence of c.8754+4A>T in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 (VUS, n=1; Likely pathogenic, n=2). Based on the evidence outlined above, the variant was classified as likely pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Apr 22, 2024 | 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. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with BRCA2-related conditions. ClinVar contains an entry for this variant (Variation ID: 220353). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in activation of a cryptic splice site and introduces a premature termination codon (PMID: 32133419; Invitae). The resulting mRNA is expected to undergo nonsense-mediated decay. This variant disrupts the c.8754+4A nucleotide in the BRCA2 gene. Other variant(s) that disrupt this nucleotide have been determined to be pathogenic (PMID: 17011978, 17924331, 20927582, 21990134, 22505045, 27433846). This suggests that this nucleotide is clinically significant, and that variants that disrupt this position are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. - |
Familial cancer of breast Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 03, 2023 | - - |
Breast-ovarian cancer, familial, susceptibility to, 2 Uncertain:1
Uncertain significance, flagged submission | clinical testing | Counsyl | Sep 07, 2016 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Benign
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DG_spliceai
Position offset: 42
DS_DL_spliceai
Position offset: -4
Find out detailed SpliceAI scores and Pangolin per-transcript scores at