13-32363178-G-C
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PP4_StrongPVS1
This summary comes from the ClinGen Evidence Repository: The c.7977-1G>C variant is an intronic variant within the native acceptor 1,2 splice site occurring in intron 17 of the BRCA2 gene. This variant is present in gnomAD v2.1 (exomes only, non-cancer subset) or gnomAD v3.1 (non-cancer subset) but is below the ENIGMA BRCA1/2 VCEP threshold >0.00002 for BS1_Supporting (PM2_Supporting, BS1, and BA1 are not met). This variant is reported to result in aberrant mRNA splicing. RT-PCR and Mini-gene assays demonstrated that the variant impacts splicing by skipping of exon 18 (PMIDs: 16211554, 28339459). Appropriate code strength determined by comparison of results to PVS1 decision tree (PVS1 (RNA) met). Multifactorial likelihood ratio analysis using clinically calibrated data produced a combined LR for this variant of 1921581780 (based on Cosegregation LR=1984740; Pathology LR=10.2; Family History LR=94.9), above the threshold for Very strong evidence towards pathogenicity (LR >350) (PP4_Very strong met; PMID:31131967, 31853058).In summary, this variant meets the criteria to be classified as a Pathogenic variant for BRCA2-related cancer predisposition based on the ACMG/AMP criteria applied as specified by the ENIGMA BRCA1/2 VCEP (PVS1 (RNA), PP4_Very strong). LINK:https://erepo.genome.network/evrepo/ui/classification/CA025372/MONDO:0012933/097
Frequency
Consequence
NM_000059.4 splice_acceptor, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 12 ACMG points.
Transcripts
RefSeq
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| BRCA2 | ENST00000380152.8 | c.7977-1G>C | splice_acceptor_variant, intron_variant | Intron 17 of 26 | 5 | NM_000059.4 | ENSP00000369497.3 | |||
| BRCA2 | ENST00000530893.7 | c.7608-1G>C | splice_acceptor_variant, intron_variant | Intron 17 of 26 | 1 | ENSP00000499438.2 | ||||
| BRCA2 | ENST00000614259.2 | n.*35-1G>C | splice_acceptor_variant, intron_variant | Intron 16 of 25 | 2 | ENSP00000506251.1 |
Frequencies
GnomAD3 genomes 0.00000658 AC: 1AN: 152072Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000401 AC: 1AN: 249640Hom.: 0 AF XY: 0.00000740 AC XY: 1AN XY: 135188
GnomAD4 exome AF: 0.00000274 AC: 4AN: 1460278Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2AN XY: 726530
GnomAD4 genome 0.00000658 AC: 1AN: 152072Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74274
ClinVar
Submissions by phenotype
Breast-ovarian cancer, familial, susceptibility to, 2 Pathogenic:6
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This c.7977-1G>C variant in intron 17 of the BRCA2 gene is predicted to alter splicing at the acceptor site of exon 18 leading to an abnormal mRNA. This variant has been reported in patients and families with hereditary breast cancer and ovarian cancer (PMID: 16211554, 20020529, 22527104, 23479189) and is rarely observed in general population databases. Therefore, the c.7977-1G>C variant in the BRCA2 gene is classified as pathogenic. -
not provided Pathogenic:4
This variant disrupts a canonical splice-acceptor site and interferes with normal BRCA2 mRNA splicing. The frequency of this variant in the general population, 0.00004 (2/50340 chromosomes, http://gnomad.broadinstitute.org), is consistent with pathogenicity. In the published literature, the variant has been reported in individuals with breast, ovarian, peritoneal, and prostate cancer (PMIDs: 28008555 (2017), 25685387 (2015), 23569316 (2013), 22006311 (2011), 20736950 (2010), 12474142 (2003)). In addition, this variant has been reported to cause aberrant splicing and loss of exon 18 (PMIDs: 28339459 (2017), 16211554 (2005)). Based on the available information, this variant is classified as pathogenic. -
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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 (Tesoriero 2005, Fraile-Bethencourt 2017); Observed in multiple families with Hereditary Breast and Ovarian Cancer (Walsh 2011, de Juan Jimenez 2013, Pritzlaff 2016); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Not observed at a significant frequency in large population cohorts (gnomAD); Also known as 8205-1G>C; This variant is associated with the following publications: (PMID: 25085752, 21769658, 21285146, 25649125, 17063265, 12474142, 20513136, 20736950, 23479189, 22006311, 22527104, 20020529, 20002770, 20043088, 22962691, 22889855, 23747895, 17981615, 27225637, 16211554, 17419707, 28008555, 28339459, 29446198, 30720243, 33084842, 32918181, 31447099, 30787465) -
Hereditary breast ovarian cancer syndrome Pathogenic:4
The c.7977-1G>C variant in BRCA2 has been reported in >100 individuals with BRCA2-associated cancers (Edwards 2003, Tesoriero 2005, Walsh 2011, Snape 2012, de Juan JimΓ©nez 2013, Bowles 2014, Breast Cancer Information Core (BIC) database) and segregated with disease in at least 1 affected family member (Tesoriero 2005). It has also been identified in 2/125752 European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs81002874); however, this frequency is low enough to be consistent with the frequency of hereditary breast and ovarian cancer (HBOC) in the general population. This variant occurs in the invariant region (+/- 1,2) of the splice consensus sequence and has been shown to cause altered splicing leading to an abnormal or absent protein (Tesoriero 2005, Fraile-Bethencourt 2017). Heterozygous loss of function of the BRCA2 gene is an established disease mechanism in HBOC. In summary, this variant meets criteria to be classified as pathogenic for hereditary breast and ovarian cancer syndrome in an autosomal dominant manner. ACMG/AMP criteria applied: PVS1; PS4; PS3_Moderate, PM2. -
Variant summary: BRCA2 c.7977-1G>C 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. At least one publication reported experimental evidence confirming that this variant affects mRNA splicing, by showing in a minigene assay several types of aberrant transcripts that exclude exon 18 (partly or fully), and no detectable canonical transcript (Fraile-Bethencourt_2017). The variant allele was found at a frequency of 4e-06 in 249640 control chromosomes (gnomAD). c.7977-1G>C has been reported in the literature in several individuals affected with breast, ovarian, and prostate cancer (e.g. Edwards_2003, Walsh_2011, Snape_2012, Jimenez_2013, Pritzlaff_2017, Dorling_2021). These data indicate that the variant is very likely to be associated with disease. 13 other submitters, including an expert panel (ENIGMA), have provided clinical-significance assessments for this variant in ClinVar after 2014 and all classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
This sequence change affects an acceptor splice site in intron 17 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 present in population databases (rs81002874, gnomAD 0.002%). Disruption of this splice site has been observed in individual(s) with prostate, ovarian, and breast cancer (PMID: 12474142, 16211554, 22006311, 23479189). This variant is also known as IVS17-1G>C or 8205-1G>C. ClinVar contains an entry for this variant (Variation ID: 38132). Based on a multifactorial likelihood algorithm using genetic, in silico, and/or statistical data, this variant has been determined to have a high probability of being pathogenic (PMID: 20020529). Studies have shown that disruption of this splice site results in skipping of exons 17-18 and skipping of exon 18, and produces a non-functional protein and/or introduces a premature termination codon (PMID: 16211554, 22006311; internal data). For these reasons, this variant has been classified as Pathogenic. -
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Hereditary cancer-predisposing syndrome Pathogenic:3
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This variant causes a G to C nucleotide substitution at the -1 position of intron 17 of the BRCA2 gene. RNA studies have shown that this variant causes aberrant transcripts which skip exon 18, resulting in frameshifts and premature translation stop signals (PMID: 22006311, 28339459). This variant has been reported in 8 individuals affected with breast cancer (including 1 male individual), 1 individual affected with both breast and ovarian cancer, 2 individuals affected with ovarian cancer, 2 individuals affected with pancreatic cancer and 4 individuals affected with prostate cancer (PMID: 15728167, 20736950, 22006311, 22527104, 22711857, 23479189, 23569316, 28008555, 32918181, 34500047, Color internal data). This variant has been detected in a breast cancer case-control meta-analysis in 4/60466 cases and 1/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA2_000488). This variant has a combined likelihood ratio for pathogenicity greater than 900:1 from individual likelihood ratios based on segregation, tumor pathology and personal and family history (PMID: 31131967, 31853058). This variant has been identified in 2/281032 chromosomes 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.7977-1G>C intronic pathogenic mutation results from a G to C substitution one nucleotide before coding exon 17 of the BRCA2 gene. This mutation has been reported in multiple individuals and families with breast and/or ovarian cancer (Tesoriero AA et al. Hum. Mutat. 2005 Nov;26:495; Snape K et al. Breast Cancer Res. Treat. 2012 Jul;134:429-33; de Juan Jiménez I et al. Fam. Cancer. 2013 Dec;12:767-77; Lai S et al. Sultan Qaboos Univ. Med. J. 2015 Feb;15:e58-70; Pritzlaff M et al. Breast Cancer Res. Treat. 2017 Feb;161:575-586) as well as prostate cancer (Edwards SM et al. Am. J. Hum. Genet. 2003 Jan;72:1-12; Mitra AV et al. BJU Int. 2007 Jun;99:1350-5; Edwards SM et al. Br. J. Cancer. 2010 Sep;103:918-24; Castro E et al. J. Clin. Oncol. 2013 May;31:1748-57; Li D et al. Front Biosci. (Landmark Ed). 2013 Jun;18:1445-59). A multifactorial likelihood ratio model that included co-segregation, pathology, co-occurrence, and family history data found this alteration to be pathogenic (Spurdle AB et al. Hum. Mutat. 2010 Feb;31:E1141-5; Parsons MT et al. Hum Mutat 2019 09;40(9):1557-1578). Of note, this alteration is also designated as IVS17-1G>C in published literature. In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site. Splicing analysis has demonstrated c.7977-1G>C results in the production of a primary transcript lacking coding exon 17 (Ambry internal data; Fraile-Bethencourt E et al. PLoS Genet. 2017 Mar;13:e1006691). 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 specified Pathogenic:1
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BRCA2-related cancer predisposition Pathogenic:1
The c.7977-1G>C variant is an intronic variant within the native acceptor 1,2 splice site occurring in intron 17 of the BRCA2 gene. This variant is present in gnomAD v2.1 (exomes only, non-cancer subset) or gnomAD v3.1 (non-cancer subset) but is below the ENIGMA BRCA1/2 VCEP threshold >0.00002 for BS1_Supporting (PM2_Supporting, BS1, and BA1 are not met). This variant is reported to result in aberrant mRNA splicing. RT-PCR and Mini-gene assays demonstrated that the variant impacts splicing by skipping of exon 18 (PMIDs: 16211554, 28339459). Appropriate code strength determined by comparison of results to PVS1 decision tree (PVS1 (RNA) met). Multifactorial likelihood ratio analysis using clinically calibrated data produced a combined LR for this variant of 1921581780 (based on Cosegregation LR=1984740; Pathology LR=10.2; Family History LR=94.9), above the threshold for Very strong evidence towards pathogenicity (LR >350) (PP4_Very strong met; PMID: 31131967, 31853058). In summary, this variant meets the criteria to be classified as a Pathogenic variant for BRCA2-related cancer predisposition based on the ACMG/AMP criteria applied as specified by the ENIGMA BRCA1/2 VCEP (PVS1 (RNA), PP4_Very strong). -
Familial cancer of breast Pathogenic:1
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Familial prostate cancer Pathogenic:1
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Hereditary breast ovarian cancer syndrome;C1838457:Fanconi anemia complementation group D1 Other:1
Variant interpreted as Pathogenic and reported on 10-16-2017 by Lab Color. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at