NM_000059.4:c.8953+1G>T
Variant summary
Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000059.4(BRCA2):c.8953+1G>T variant causes a splice donor, intron change. The variant allele was found at a frequency of 0.000000685 in 1,459,830 control chromosomes in the GnomAD database, with no homozygous occurrence. 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
Publications
- breast-ovarian cancer, familial, susceptibility to, 2Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), ClinGen
- Fanconi anemia complementation group D1Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, ClinGen, G2P
- pancreatic cancer, susceptibility to, 2Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
- sarcomaInheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
- hereditary breast ovarian cancer syndromeInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- Fanconi anemiaInheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
- medulloblastomaInheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
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ACMG classification
Our verdict: Pathogenic. The variant received 18 ACMG points.
Transcripts
RefSeq
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| BRCA2 | ENST00000380152.8 | c.8953+1G>T | splice_donor_variant, intron_variant | Intron 22 of 26 | 5 | NM_000059.4 | ENSP00000369497.3 | |||
| BRCA2 | ENST00000530893.7 | c.8584+1G>T | splice_donor_variant, intron_variant | Intron 22 of 26 | 1 | ENSP00000499438.2 | ||||
| BRCA2 | ENST00000614259.2 | n.*1011+1G>T | splice_donor_variant, intron_variant | Intron 21 of 25 | 2 | ENSP00000506251.1 |
Frequencies
GnomAD3 genomes
GnomAD4 exome AF: 6.85e-7 AC: 1AN: 1459830Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 726144 show subpopulations
GnomAD4 genome
ClinVar
Submissions by phenotype
Breast-ovarian cancer, familial, susceptibility to, 2 Pathogenic:8
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This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -
IARC class based on posterior probability from multifactorial likelihood analysis, thresholds for class as per Plon et al. 2008 (PMID: 18951446). Class 5 based on posterior probability = 1 -
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PVS1 (RNA); PM2_Supporting; PP4strong -
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The c.8953+1G>T variant in the BRCA2 gene is located at the canonical splice site of intron 22 and is predicted to inflict donor loss (SpliceAI delta score: 0.99), resulting in aberrant splicing and disrupted protein product. The variant has been reported in multiple individuals with breast/ovarian/prostate cancer (PMID: 31209999, 32022259, 32614418, 21394826, 36045058, 18465347). Functional minigene splicing assay and RNA analysis showed aberrant transcripts and negative functional impact (PMID: 25382762, 21394826). Loss-of-function variants of BRCA2 are known to be pathogenic (PMID: 8988179, 11897832, 29446198). The variant is reported in ClinVar as pathogenic (ID: 38198) and reviewed by the expert panel. The variant is absent in the general population database (gnomAD). Therefore, the c.8953+1G>T variant of BRCA2 has been classified as pathogenic. -
Hereditary breast ovarian cancer syndrome Pathogenic:4
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The c.8953+1G>T variant in BRCA2 has been reported in 3 individuals with BRCA2-a ssociated cancers (Borg 2010, Breast Cancer Information Core (BIC) database) and was absent from large population studies. This variant occurs in the invariant region (+/- 1,2) of the splice consensus sequence and is predicted to cause alte red splicing leading to an abnormal or absent protein. In vitro functional studi es provide some evidence that the c.8953+1G>T variant impacts splicing (Whiley 2 011, Acedo 2015). Heterozygous loss of function of the BRCA2 gene is an establis hed disease mechanism in individuals with hereditary breast and ovarian cancer ( HBOC). In addition, this variant was classified as Pathogenic on August 10, 2015 by the ClinGen-approved ENIGMA expert panel (ClinVar SCV000244490.1). In summar y, the c.8953+1G>T variant meets our criteria to be classified as pathogenic for HBOC in an autosomal dominant manner based upon absence from controls, function al evidence, and the predicted impact to the protein. -
Variant summary: BRCA2 c.8953+1G>T 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. At least one publication reports experimental evidence that this variant affects mRNA splicing. These predictions have been confirmed by functional studies that showed variant lead to exon 22 skipping (Whiley_2011 and Acedo_2014). The variant was absent in 248098 control chromosomes. c.8953+1G>T has been reported in the literature in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (eg. Borg_2010, Thomassen_2008, Whiley_2011, Nielsen_2017, Sharma_2015, Euhus_2002, etc). These data indicate that the variant is likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 21990134, 20104584, 21394826, 18465347, 12048272, 25382762, 26360800, 26004055). 11 submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
This sequence change affects a donor splice site in intron 22 of the BRCA2 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or altered protein product. This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with breast cancer (PMID: 2010458, 21394826, 26187060). This variant is also known as 9181+1G>T and IVS22+1G>T. ClinVar contains an entry for this variant (Variation ID: 38198). An algorithm developed specifically for the BRCA2 gene suggests that this missense change is likely to be deleterious (PMID: 21990134). Studies have shown that disruption of this splice site results in skipping of exon 22 and activation of a cryptic splice site, which introduces a premature termination codon (PMID: 21394826; Invitae). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. -
not provided Pathogenic:3
The BRCA2 c.8953+1G>T variant disrupts a canonical splice-donor site and interferes with normal BRCA2 mRNA splicing. This variant has been reported in the published literature in individuals with prostate cancer (PMID: 26360800 (2016), 36045058 (2023)) and breast and/or ovarian cancer (PMID: 20104584 (2010), 26004055 (2016), 32022259 (2020), 32939053 (2020)). In vitro splicing assays demonstrated that this variant results in aberrant BRCA2 mRNA splicing (PMID: 21394826 (2011) and 25382762 (2015)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Based on the available information, this variant is classified as pathogenic. -
BRCA2: PVS1, PM2 -
Canonical splice site variant in a gene for which loss-of-function is a known mechanism of disease; Observed in individuals with BRCA2-related cancers (Borg 2010, Whiley 2011, Sharma 2016, Roed Nielsen 2016); Published functional studies demonstrate a damaging effect: multiple aberrant transcripts, with skipping of exon 22 being the most prevalent (Whiley 2011, Acedo 2015); Multifactorial studies suggest this variant is associated with breast and ovarian cancer (Lindor 2012); Considered pathogenic by a well-established clinical consortium and/or database; Not observed at significant frequency in large population cohorts (gnomAD); Also known as BRCA2 9181+1G>T; This variant is associated with the following publications: (PMID: 20104584, 29922827, 32022259, 21990134, 26004055, 25382762, 26360800, 29164420, 21394826, 29446198, 31209999, 31263571) -
Hereditary cancer-predisposing syndrome Pathogenic:3
This variant causes a G to T nucleotide substitution at the +1 position of intron 22 of the BRCA2 gene. RNA studies have shown that this variant causes out-of-frame splicing, resulting in premature termination (PMID: 21394826, 25382762). This variant is expected to result in an absent or non-functional protein product. This variant has been reported in at least three individuals affected with breast or ovarian cancer (PMID: 29164420, 32022259; Color internal data), an individual affected with prostate cancer (PMID: 26360800) and suspected hereditary cancer families (PMID: 21394826, 31209999). 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. -
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The c.8953+1G>T intronic pathogenic mutation results from a G to T substitution one nucleotide after coding exon 21 of the BRCA2 gene. Multiple RNA studies with patient material and with a minigene assay have identified skipping of coding exon 21 (also known as Exon 22 in the literature) as the major event produced by this alteration (Ambry internal data; Acedo A et al. Hum Mutat, 2015 Feb;36:210-21; Whiley P et al. Hum Mutat. 2011 Jun;32(6):678-87). This alteration has been reported in a woman with asynchronous contralateral breast cancer; an individual with prostate cancer, and an individual with metachronous early onset breast cancer and tubulovillous adenoma of the papilla of Vater (Borg A et al. Hum Mutat. 2010 Mar;31(3):E1200-40;Roed Nielsen H et al. Acta Oncol, 2016 Sep;55:38-44; Sharma MB et al. Acta Oncol, 2016 May;55:377-81). This alteration has been classified as pathogenic (p>0.96) by multifactorial analysis, which integrates the following lines of evidence to produce a quantitative likelihood of pathogenicity: in silico prediction models, segregation with disease, tumor characteristics, mutation co-occurrence, and functional assay results (Lindor NM et al. Hum Mutat. 2012;33(1):8-21). 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. -
Familial cancer of breast Pathogenic:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at