rs80359803
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Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2PP5_Very_Strong
The NM_000059.4(BRCA2):c.8754G>A(p.Glu2918Glu) variant causes a splice region, synonymous change. The variant allele was found at a frequency of 0.00000137 in 1,461,736 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000014 ( 0 hom. )
Consequence
BRCA2
NM_000059.4 splice_region, synonymous
NM_000059.4 splice_region, synonymous
Scores
2
Splicing: ADA: 0.9983
2
Clinical Significance
Conservation
PhyloP100: 6.08
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 13-32376791-G-A is Pathogenic according to our data. Variant chr13-32376791-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 52671.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-32376791-G-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| BRCA2 | ENST00000380152.8 | c.8754G>A | p.Glu2918Glu | splice_region_variant, synonymous_variant | 21/27 | 5 | NM_000059.4 | ENSP00000369497.3 | ||
| BRCA2 | ENST00000530893.7 | c.8385G>A | p.Glu2795Glu | splice_region_variant, synonymous_variant | 21/27 | 1 | ENSP00000499438.2 | |||
| BRCA2 | ENST00000614259.2 | n.*812G>A | splice_region_variant, non_coding_transcript_exon_variant | 20/26 | 2 | ENSP00000506251.1 | ||||
| BRCA2 | ENST00000614259 | n.*812G>A | 3_prime_UTR_variant | 20/25 | 2 | ENSP00000506251.1 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
32
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 250952Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135656
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GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461736Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1AN XY: 727160
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:10
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Hereditary breast ovarian cancer syndrome Pathogenic:4
| Likely pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Dec 15, 2022 | Variant summary: BRCA2 c.8754G>A (p.Glu2918Glu) alters the conserved last nucleotide of exon 21 and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Two predict the variant abolishes a 5' splicing donor site. Two predict the variant weakens a 5' donor site. At least one publication reports experimental evidence that this variant affects mRNA splicing, leading to a shift in the reading frame (Acedo_2015). The variant allele was found at a frequency of 4e-06 in 250952 control chromosomes. c.8754G>A has been reported in the literature in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (examples: Sambiasi_2014 Kaur_2018, Rebbeck_2018, Finkelman_2012). These data indicate that the variant is likely to be associated with disease. Five 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 likely pathogenic. - |
| Pathogenic, no assertion criteria provided | research | Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto | Jan 31, 2014 | - - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jul 07, 2023 | This variant is present in population databases (rs80359803, gnomAD 0.003%). 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. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 25382762). ClinVar contains an entry for this variant (Variation ID: 52671). This variant is also known as E2918E. This variant has been observed in individual(s) with breast and/or ovarian cancer (PMID: 22430266, 24145998, 29700634, 31454914). This sequence change affects codon 2918 of the BRCA2 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the BRCA2 protein. This variant also falls at the last nucleotide of exon 21, which is part of the consensus splice site for this exon. - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | May 15, 2023 | The p.Glu2918Glu variant in BRCA2 has been reported in at least 13 individuals with BRCA2-associated cancers, including at least 1 male with breast cancer, and segregated with disease in 2 affected relatives from 1 family (Kaur 2018 PMID: 29700634, Millan Catalan 2019 PMID: 31454914, Bapat 2021 medRxiv 2021.07.01.21258680; doi: https://doi.org/10.1101/2021.07.01.21258680). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID 52671) and was absent from large population studies. Although it is a synonymous (silent) variant, it is located in the last three bases of the exon, which is part of the 5’ splice region. Computational tools predict a splicing impact, which is corroborated by an in vitro minigene assay that indicates that this synonymous change disrupts normal splicing and results in an aberrant transcript that is subjected to nonsense-mediated decay (Acedo 2015 PMID: 25382762). In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant hereditary breast and ovarian cancer (HBOC). ACMG/AMP Criteria applied: PS4, PM2_Supporting, PP3, PS3_Supporting. - |
Breast-ovarian cancer, familial, susceptibility to, 2 Pathogenic:3
| Pathogenic, no assertion criteria provided | clinical testing | Breast Cancer Information Core (BIC) (BRCA2) | Nov 10, 2000 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Sharing Clinical Reports Project (SCRP) | Apr 15, 2010 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge | Oct 02, 2015 | - - |
not provided Pathogenic:2
| Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jul 13, 2017 | This variant is denoted BRCA2 c.8754G>A at the DNA level. Although the variant is silent at the codinglevel, preserving a Glutamic Acid at codon 2918, it has been demonstrated to cause abnormal splicing. Located at thelast nucleotide of exon 21, it disrupts a natural splice donor site and was found to cause abnormal splicing wheninterrogated via minigene assay (Acedo 2014). This variant, also reported as BRCA2 8982G>A using alternatenomenclature, has been published in at least one individual reported to have Hereditary Breast and Ovarian Cancersyndrome (Finkelman 2012). In addition, nearby variants found to cause the same impact on splicing have beenreported in association with Hereditary Breast and Ovarian Cancer (Brandão 2011). BRCA2 c.8754G>A was notobserved in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek2016). The nucleotide which is altered, a guanine (G) at base 8754, is conserved across species. Based on currentlyavailable information, we consider BRCA2 c.8754G>A to be likely pathogenic - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Oct 27, 2022 | This variant disrupts a canonical splice-donor site and interferes with normal BRCA2 mRNA splicing. The frequency of this variant in the general population, 0.000004 (1/250952 chromosomes, http://gnomad.broadinstitute.org), is consistent with pathogenicity. In the published literature, the variant has been reported in individuals affected with breast cancer (PMID: 29700634 (2018), 31454914 (2019)). It was also identified in individuals at-risk for breast/ovarian cancer (PMID: 22430266 (2012), 29446198 (2018)). Additionally, the authors of an in vitro minigene study observed that the variant abrogated the splice site completely and inserted noncoding sequence from the intron, including a premature stop codon, into the mRNA (PMID: 25382762 (2015)). Based on the available information, this variant is classified as pathogenic. - |
Hereditary cancer-predisposing syndrome Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 24, 2021 | The c.8754G>A pathogenic variant (also known as p.E2918E), located in coding exon 20 of the BRCA2 gene, results from a G to A substitution at nucleotide position 8754. This nucleotide substitution does not change the glutamic acid at codon 2918. However, this change occurs in the last base pair of coding exon 20, which makes it likely to have some effect on normal mRNA splicing. This alteration has been reported in numerous breast cancer cohorts (Finkelman BS et al. J. Clin. Oncol., 2012 Apr;30:1321-8; Kaur RP et al. Med. Oncol., 2018 Apr;35:81; Rebbeck TR et al. Hum. Mutat., 2018 05;39:593-620; Millan Catalan O et al. Cancers (Basel), 2019 Aug;11:). Multiple different RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data; Acedo A et al. Hum. Mutat., 2015 Feb;36:210-21). In addition, many other non-canonical splice alterations have been identified at this donor site and are also known to lead to a complete aberrant splice defect (Colombo M et al. PLoS One, 2013 Feb;8:e57173; Brandão RD et al. Breast Cancer Res Treat, 2011 Oct;129:971-82; Wangensteen T et al. Hered Cancer Clin Pract, 2019 May;17:14; Bonatti F et al. Cancer Genet Cytogenet, 2006 Oct;170:93-101; Houdayer C et al. Hum Mutat, 2012 Aug;33:1228-38; Acedo A et al. Hum Mutat, 2015 Feb;36:210-21; Hendriks G et al. Hum Mutat, 2014 Nov;35:1382-91). 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. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
CADD
Uncertain
DANN
Benign
Splicing
Name
Calibrated prediction
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Prediction
dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Pathogenic
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DG_spliceai
Position offset: 46
DS_DL_spliceai
Position offset: 0
Find out detailed SpliceAI scores and Pangolin per-transcript scores at