rs276174916
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000059.4(BRCA2):c.8954-1_8955delGTTinsAA(p.Val2985fs) variant causes a frameshift, splice acceptor, missense, splice region, intron change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Pathogenic in Lovd. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V2985E) has been classified as Pathogenic. Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_000059.4 frameshift, splice_acceptor, missense, splice_region, 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.8954-1_8955delGTTinsAA | p.Val2985fs | frameshift_variant, splice_acceptor_variant, missense_variant, splice_region_variant, intron_variant | Exon 23 of 27 | 5 | NM_000059.4 | ENSP00000369497.3 | ||
| BRCA2 | ENST00000530893.7 | c.8585-1_8586delGTTinsAA | p.Val2862fs | frameshift_variant, splice_acceptor_variant, missense_variant, splice_region_variant, intron_variant | Exon 23 of 27 | 1 | ENSP00000499438.2 | |||
| BRCA2 | ENST00000614259.2 | n.*1012-1_*1013delGTTinsAA | splice_region_variant, non_coding_transcript_exon_variant | Exon 22 of 26 | 2 | ENSP00000506251.1 | ||||
| BRCA2 | ENST00000614259 | n.*1012-1_*1013delGTTinsAA | splice_acceptor_variant, 3_prime_UTR_variant, intron_variant | Exon 22 of 25 | 2 | ENSP00000506251.1 |
Frequencies
GnomAD3 genomes
GnomAD4 genome
ClinVar
Submissions by phenotype
Breast-ovarian cancer, familial, susceptibility to, 2 Pathogenic:3
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 = 0.993615 -
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This variant, c.8954-1_8955delGTTinsAA, is a complex sequence change that affects an acceptor splice site in intron 22 of the BRCA2 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. Loss-of-function variants in BRCA2 are known to be pathogenic. The variant was absent in 250792 control chromosomes (gnomAD).This alteration has been identified in numerous individuals from breast and ovarian cancer families (PMID: 28152038, 28476184, 22632462, 19996028, 23451180, 31341520, 31131967, 33484353, 32438681). In silico splice site analysis predicts that this alteration will weaken the native splice donor site. Experimental in vitro studies variant have shown that this complex change results in exon skipping (PMID: 23451180, 22632462). For these reasons, this variant has been classified as Pathogenic. -
Hereditary cancer-predisposing syndrome Pathogenic:2
The c.8954-1_8955delGTTinsAA pathogenic mutation, located in intron 22/exon 23 (also known as intron 21/coding exon 22) of the BRCA2 gene, results from the deletion of 3 nucleotides (GTT) and insertion of 2 nucleotides (AA) between position c.8954-1 and c.8955 leading to the disruption of the native canonical splice acceptor site. This alteration has been identified in numerous individuals from breast and ovarian cancer families (Laitman Y. Hum Mutat. 2019 11;40(11):e1-e23.; Marchetti C. Ann Surg Oncol. 2018 Nov;25(12):3701-3708; Vietri MT. Med Oncol. 2021 Jan;38(2): 13; Lai KN. BMC Cancer. 2017 02;17(1):149; Oktay K et al. J Clin Oncol. 2010;28(2):240-4). This alteration was also classified as pathogenic in a multifactorial model of variant interpretation that incorporates co-segregation, family history, co-occurrence and tumor pathology and case-control data (Parsons MT et al. Hum Mutat . 2019 Sep;40(9):1557-1578). In silico splice site analysis predicts that this alteration will weaken the native splice donor site. Multiple RNA studies have shown that this alteration leads primarily to a transcript with a 51 nucleotide deletion in coding exon 22 (also called exon 23 in the literature: Ambry internal data; Acedo A et al. Breast Cancer Res. 2012;14(3):R87). The resulting transcript is expected to produce a protein with an in-frame loss of 17 amino acids. Based on internal structural analysis, this protein, V2985_T3001del, is expected to be deleterious as it is strongly untolerated and is more untolerated than remote pathogenic variants and benign variants (Ambry internal data). Furthermore, functional studies with this a peptide containing this deletion show it has impaired binding to DSS1 and single-stranded DNA (Colombo M et al. PLoS One. 2013;8(2):e57173). Of note, this alteration is also referred to as IVS22-1del3insAA and IVS22-1delGTTinsAA in published literature. 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 pathogenic. -
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Familial cancer of breast Pathogenic:2
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This variant, c.8954-1_8955delGTTinsAA, is a complex sequence change that affects an acceptor splice site in intron 22 of the BRCA2 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. Loss-of-function variants in BRCA2 are known to be pathogenic. The variant was absent in 250792 control chromosomes (gnomAD).This alteration has been identified in numerous individuals from breast and ovarian cancer families (PMID: 28152038, 28476184, 22632462, 19996028, 23451180, 31341520, 31131967, 33484353, 32438681). In silico splice site analysis predicts that this alteration will weaken the native splice donor site. Experimental in vitro studies variant have shown that this complex change results in exon skipping (PMID: 23451180, 22632462). For these reasons, this variant has been classified as Pathogenic. -
Hereditary breast ovarian cancer syndrome Pathogenic:2
This sequence change affects a splice site in intron 22 of the BRCA2 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in BRCA2 are known to be pathogenic (PMID: 20104584). Information on the frequency of this variant in the gnomAD database is not available, as this variant may be reported differently in the database. Disruption of this splice site has been observed in individual(s) with breast cancer, occult primary ovarian insufficiency, and endometrial cancer (PMID: 19996028, 33484353). This variant is also known as IVS22-1del3insAA or c.8954-1_8955delGTTinsAA. Algorithms developed to predict the effect of variants on gene product structure and function are not available or were not evaluated for this variant. Experimental studies have shown that disruption of this splice site affects BRCA2 function (PMID: 23451180). For these reasons, this variant has been classified as Pathogenic. -
Variant summary: BRCA2 c.8954-1_8955delinsAA 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 3' acceptor site. Experimental evidence support these predictions indicating the variant results in various aberrant transcripts, with the main one being a deletion of 51 nucleotides at the 5'-end of exon 23 with consequent 17-amino acids loss, which was demonstrated to abrogate the ability of BRCA2 to bind the DSS1 protein and its affinity for ssDNA (Acedo_2012, Colombo_2013). The variant was absent in 250792 control chromosomes (gnomAD). c.8954-1_8955delinsAA has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer (e.g. Arvai_2019, Marchetti_2018, Oktay_2010, Rebbeck_2018). These data indicate that the variant is likely to be associated with disease. Four ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
BRCA2-related cancer predisposition Pathogenic:1
The c.8954-1_8955delinsAA variant in the BRCA2 gene is located at the canonical splice site of intron 22 and is predicted to inflict acceptor loss (SpliceAI delta score: 0.90), resulting in alternative splicing and disrupted protein product. The variant has been reported in individuals with breast/ovarian/prostate cancer (PMID: 33484353, 30128899, 33573335, 27616075). Experimental RNA analysis and minigene assay show that the variant causes aberrant transcripts and have deleterious impact on function (PMID: 23451180, 27060066, 22632462). Loss-of-function variants in the BRCA2 gene are known to cause hereditary breast and ovarian cancer (PMID: 8988179, 11897832, 29446198). This variant has been reported in ClinVar as pathogenic by the expert panel (ID: 142095). The variant is absent in the general population database (gnomAD). Therefore, the c.8954-1_8955delinsAA variant in the BRCA2 gene has been classified as pathogenic. -
not provided Pathogenic:1
Canonical splice site variant predicted to result in a null allele in a gene for which loss of function is a known mechanism of disease (Acedo 2012, Colombo 2013); Observed in individuals with a personal and/or family history consistent with pathogenic variants in this gene and other cancers in published literature (Oktay 2010, Johnson 2017, Santonocito 2020, Vietri 2021); Multifactorial likelihood analysis suggests this variant is pathogenic (Parsons 2019); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Not observed at significant frequency in large population cohorts (gnomAD); Also known as 9182-1_9183delGTTinsAA; This variant is associated with the following publications: (PMID: 28152038, 28476184, 22632462, 19996028, 23451180, 31341520, 31131967, 33484353, 32438681) -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at