rs80359403
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000059.4(BRCA2):c.3744_3747del(p.Ser1248ArgfsTer10) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000186 in 1,610,320 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★★). Synonymous variant affecting the same amino acid position (i.e. S1248S) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_000059.4 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
BRCA2 | NM_000059.4 | c.3744_3747del | p.Ser1248ArgfsTer10 | frameshift_variant | 11/27 | ENST00000380152.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BRCA2 | ENST00000380152.8 | c.3744_3747del | p.Ser1248ArgfsTer10 | frameshift_variant | 11/27 | 5 | NM_000059.4 | A2 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152196Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000406 AC: 1AN: 246600Hom.: 0 AF XY: 0.00000751 AC XY: 1AN XY: 133160
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1458124Hom.: 0 AF XY: 0.00000138 AC XY: 1AN XY: 724946
GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152196Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74358
ClinVar
Submissions by phenotype
Breast-ovarian cancer, familial, susceptibility to, 2 Pathogenic:8
Pathogenic, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Mar 23, 2023 | This variant deletes 4 nucleotides in exon 11 of the BRCA2 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been observed in over twenty individuals affected with breast cancer and is known to be a recurrent disease-causing mutation in the Korean population (PMID: 25863477, 26187060, 28205045, 34063308). This variant has been identified in 1/246600 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. - |
Pathogenic, no assertion criteria provided | clinical testing | Breast Cancer Information Core (BIC) (BRCA2) | May 29, 2002 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Sharing Clinical Reports Project (SCRP) | Feb 26, 2010 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | MGZ Medical Genetics Center | Nov 12, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Division of Medical Genetics, University of Washington | Mar 07, 2020 | This variant leads to a translational frameshift and the introduction of a premature termination codon at position 10 of the new reading frame. The variant transcript is predicted to be unstable and degraded by nonsense-mediated decay. Loss of expression of one allele of BRCA2 is a well-established mechanism of disease for Hereditary Breast and Ovarian cancer (Borg 2010). This variant has been reported in the literature in multiple individuals and families with breast and/or ovarian cancer (Meindl 2001, Ahn 2007, Machackova 2008, Seong 2009, Kwong 2016). This variant has an allele frequency of 0.000004 in the Broad Institute gnomAD Browser (https://gnomad.broadinstitute.org/). Thus, this variant is interpreted as pathogenic. PS4-moderate; PVS1 - |
Pathogenic, criteria provided, single submitter | clinical testing | Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge | Oct 02, 2015 | - - |
Pathogenic, reviewed by expert panel | curation | Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) | Apr 22, 2016 | Variant allele predicted to encode a truncated non-functional protein. - |
Pathogenic, no assertion criteria provided | clinical testing | BRCAlab, Lund University | Aug 26, 2022 | - - |
not provided Pathogenic:5
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Mar 01, 2022 | BRCA2: PVS1, PM2, PS4:Moderate - |
Pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Nov 12, 2020 | This variant has been reported in individuals affected with breast cancer, prostate cancer, and ovarian cancer in the published literature (PMID: 28724667 (2017), 28205045 (2017), 28049253 (2017), 26306726 (2015), 26187060 (2015), 25863477 (2015), 22798144 (2012)). Based on the available information, this variant is classified as pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jun 30, 2020 | Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Observed in several individuals with personal and family history of Hereditary Breast and Ovarian Cancer syndrome and is a recurrent variant in the Korean population (Kang 2002, Meindl 2002, Kim 2012, Minucci 2015, Kwong 2016, Song 2017); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Not observed in large population cohorts (Lek 2016); Also known as 3972_3975delTGAG and 3972del4; This variant is associated with the following publications: (PMID: 25007954, 28724667, 26295337, 11802209, 19499246, 19656164, 12204006, 17100994, 16455195, 18489799, 17851763, 22798144, 22217648, 22382806, 24155753, 26187060, 28049253, 26709275, 26306726, 28392550, 28205045, 29673794, 28111427, 30720243, 30702160, 28726808, 31214711) - |
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Sep 21, 2022 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Clinical Genetics and Genomics, Karolinska University Hospital | Apr 03, 2018 | - - |
Hereditary breast ovarian cancer syndrome Pathogenic:4
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jul 28, 2022 | Variant summary: BRCA2 c.3744_3747delTGAG (p.Ser1248ArgfsX10) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 4.1e-06 in 246600 control chromosomes (gnomAD). c.3744_3747delTGAG has been reported in the literature in multiple individuals affected with Hereditary Breast And/or Ovarian Cancer (examples: Kang_2015, Minucci_2015 and Song_2017). These data indicate that the variant is very likely to be associated with disease. Thirteen submitters including an expert panel (ENIGMA) have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Pathogenic, no assertion criteria provided | research | Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto | Jan 31, 2014 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Mendelics | Jul 02, 2018 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 29, 2023 | This sequence change creates a premature translational stop signal (p.Ser1248Argfs*10) in the BRCA2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in BRCA2 are known to be pathogenic (PMID: 20104584). This variant is present in population databases (rs80359403, gnomAD 0.006%). This premature translational stop signal has been observed in individual(s) with breast/ovarian cancer (PMID: 11802209, 16455195, 18489799, 19656164, 26187060). This variant is also known as 3972del4. ClinVar contains an entry for this variant (Variation ID: 37856). For these reasons, this variant has been classified as Pathogenic. - |
Hereditary cancer-predisposing syndrome Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 14, 2022 | The c.3744_3747delTGAG pathogenic mutation, located in coding exon 10 of the BRCA2 gene, results from a deletion of 4 nucleotides at nucleotide positions 3744 to 3747, causing a translational frameshift with a predicted alternate stop codon (p.S1248Rfs*10). This alteration has been reported in multiple breast and/or ovarian cancer families (Foretova L et al. Hum. Mutat. 2004 Apr;23:397-8; Li WF et al. Breast Cancer Res. Treat. 2008 Jul;110:99-109; Jang JH et al. J. Hum. Genet. 2012 Mar;57:212-5; Song WH et al. J. Korean Med. Sci. 2017 Feb;32:377-381; Park B et al. Breast Cancer Res. Treat. 2017 May;163:139-150; Concolino P et al. Int J Mol Sci, 2019 Jul;20:; Bang YJ et al. Cancer Res Treat, 2021 Oct;:). Of note, this alteration is also designated as 3972_3975delTGAG and 3972del4 in published literature. In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. - |
Pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Jan 25, 2023 | This variant deletes 4 nucleotides in exon 11 of the BRCA2 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been observed in over twenty individuals affected with breast cancer and is known to be a recurrent disease-causing mutation in the Korean population (PMID: 25863477, 26187060, 28205045, 34063308). This variant has been identified in 1/246600 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. - |
not specified Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Feb 14, 2019 | The BRCA2 c.3744_3747delTGAG; p.Ser1248fs variant (rs80359403) is reported in the literature in numerous individuals with a personal or family history of breast and/or ovarian cancer (Machackova 2008, Meindl 2002, Park 2016, Park 2017, Seong 2009). This variant is found on a single chromosome in the Genome Aggregation Database, indicating it is not a common polymorphism, and it is reported as pathogenic by numerous laboratories in ClinVar (Variation ID: 37856). This variant causes a frameshift by deleting four nucleotides, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered to be pathogenic. References: Machackova E et al. Spectrum and characterisation of BRCA1 and BRCA2 deleterious mutations in high-risk Czech patients with breast and/or ovarian cancer. BMC Cancer. 2008 May 20;8:140. Meindl A et al. Comprehensive analysis of 989 patients with breast or ovarian cancer provides BRCA1 and BRCA2 mutation profiles and frequencies for the German population. Int J Cancer. 2002 Feb 1;97(4):472-80. Park B et al. Characteristics of BRCA1/2 mutations carriers including large genomic rearrangements in high risk breast cancer patients. Breast Cancer Res Treat. 2017 May;163(1):139-150. Park J et al. Comparison of Targeted Next-Generation and Sanger Sequencing for the BRCA1 and BRCA2 Mutation Screening. Ann Lab Med. 2016 Mar;36(2):197-201. Seong MW et al. Comprehensive mutational analysis of BRCA1/BRCA2 for Korean breast cancer patients: evidence of a founder mutation. Clin Genet. 2009 Aug;76(2):152-60. - |
Medulloblastoma;C0346153:Familial cancer of breast;C0376358:Malignant tumor of prostate;C1838457:Fanconi anemia complementation group D1;C2675520:Breast-ovarian cancer, familial, susceptibility to, 2;C2751641:Glioma susceptibility 3;C3150546:Pancreatic cancer, susceptibility to, 2;CN033288:Wilms tumor 1 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 20, 2021 | - - |
Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Department of Molecular Diagnostics, Institute of Oncology Ljubljana | Apr 02, 2020 | - - |
Familial cancer of breast Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Sep 09, 2023 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at