rs80359543
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000059.4(BRCA2):c.5851_5854del(p.Ser1951TrpfsTer11) 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 1,613,762 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. V1950V) 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.5851_5854del | p.Ser1951TrpfsTer11 | frameshift_variant | 11/27 | ENST00000380152.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BRCA2 | ENST00000380152.8 | c.5851_5854del | p.Ser1951TrpfsTer11 | frameshift_variant | 11/27 | 5 | NM_000059.4 | A2 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152210Hom.: 0 Cov.: 33
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461552Hom.: 0 AF XY: 0.00000138 AC XY: 1AN XY: 727046
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152210Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74360
ClinVar
Submissions by phenotype
Breast-ovarian cancer, familial, susceptibility to, 2 Pathogenic:8
Pathogenic, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The BRCA2 p.Ser1951TrpfsX11 variant was identified in 9 of 3458 proband chromosomes (frequency: 0.008) from individuals with breast cancer or hereditary breast and ovarian cancer families (Diez 2003 12955716, Juwle 2012, Kurian 2008, Lubinski 2004, Papi 2009, Vaidyanathan 2009). The variant was not detected in 500 control chromosomes from healthy individuals from these studies. The variant was also identified in dbSNP (ID: rs80359543), LOVD, UMD (6X as a causal variant), and the BIC database (11X with clinical importance). The p.Ser1951TrpfsX11 deletion variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 1951and leads to a premature stop codon 11 codons downstream. This alteration is then predicted to result in a truncated or absent protein and loss of function. Loss of function variants of the BRCA2 gene are an established mechanism of disease in hereditary breast and ovarian cancer and is the type of variant expected to cause the disorder. In summary, based on the above information, this variant meets our laboratory’s criteria to be 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) | May 01, 2012 | - - |
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, criteria provided, single submitter | clinical testing | Pars Genome Lab | Aug 09, 2021 | We found this variant in a 67-year-old female with unilateral breast cancer with family history of breast cancer. - |
Pathogenic, reviewed by expert panel | curation | Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) | Sep 08, 2016 | Variant allele predicted to encode a truncated non-functional protein. - |
Likely pathogenic, criteria provided, single submitter | literature only | Counsyl | Sep 04, 2014 | - - |
Pathogenic, no assertion criteria provided | clinical testing | BRCAlab, Lund University | Mar 02, 2020 | - - |
not provided Pathogenic:4
Pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | May 14, 2021 | This frameshift variant causes the premature termination of BRCA2 protein synthesis. In addition, it has been reported in individuals affected with breast and/or ovarian cancer in the published literature (PMID: 32854451 (2020), 30702160 (2019), 29487695 (2018), 29470806 (2018), 29335924 (2018), 29084914 (2018), 26183948 (2015)). Based on the available information, this variant is classified as pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | May 17, 2017 | The BRCA2 c.5851_5854delAGTT; p.Ser1951fs variant (also known as 6079delAGTT) has been reported in several individuals with hereditary breast and ovarian cancer syndrome (Dodova 2015, Juwle 2012, Kwong 2012, Papi 2009, Vaidyanathan 2009). This variant is reported in ClinVar (Variation ID: 38001), and is absent from the general population databases (1000 Genomes Project, Exome Variant Server, Genome Aggregation Database). This variant creates a frameshift and is predicted to result in a truncated protein or absent transcript, and is considered pathogenic. REFERENCES Link to ClinVar database for c.5851_5854delAGTT: https://www.ncbi.nlm.nih.gov/clinvar/variation/38001/ Dodova RI et al. Spectrum and frequencies of BRCA1/2 mutations in Bulgarian high risk breast cancer patients. BMC Cancer. 2015 Jul 17;15:523. Juwle A et al. BRCA1/BRCA2 gene mutations/SNPs and BRCA1 haplotypes in early-onset breast cancer patients of Indian ethnicity. Med Oncol. 2012 Dec;29(5):3272-81. Kwong A et al. Identification of BRCA1/2 founder mutations in Southern Chinese breast cancer patients using gene sequencing and high resolution DNA melting analysis. PLoS One. 2012;7(9):e43994. Papi L et al. Founder mutations account for the majority of BRCA1-attributable hereditary breast/ovarian cancer cases in a population from Tuscany, Central Italy. Breast Cancer Res Treat. 2009 Oct;117(3):497-504. Vaidyanathan K et al. BRCA1 and BRCA2 germline mutation analysis among Indian women from south India: identification of four novel mutations and high-frequency occurrence of 185delAG mutation. J Biosci. 2009 Sep;34(3):415-22. - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jan 24, 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; Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Observed in association with breast and/or ovarian cancer (Dez 2003, Kwong 2009, Papi 2009, Vaidyanathan 2009, Juwle 2012, Dodova 2015); Not observed in large population cohorts (Lek et al., 2016); Also known as 6079del4 or 6079_6082delAGTT; This variant is associated with the following publications: (PMID: 25893891, 10660329, 19353265, 18821011, 22752604, 15131399, 26183948, 26681312, 18528753, 22970155, 26187060, 19805903, 12955716, 29335924, 29084914, 29470806, 30128899, 29487695, 11920621, 30702160, 32854451) - |
Pathogenic, criteria provided, single submitter | clinical testing | Clinical Genetics and Genomics, Karolinska University Hospital | Sep 30, 2016 | - - |
Hereditary cancer-predisposing syndrome Pathogenic:3
Pathogenic, criteria provided, single submitter | curation | Sema4, Sema4 | Dec 17, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 09, 2022 | The c.5851_5854delAGTT pathogenic mutation, located in coding exon 10 of the BRCA2 gene, results from a deletion of 4 nucleotides at nucleotide positions 5851 to 5854, causing a translational frameshift with a predicted alternate stop codon (p.S1951Wfs*11). This alteration has been reported in multiple breast and/or ovarian cancer families across various ethnicities (Kwong A et al. Breast Cancer Res. Treat. 2009 Oct;117:683-6; Papi L et al. Breast Cancer Res. Treat. 2009 Oct;117:497-504; Vaidyanathan K et al. J. Biosci. 2009 Sep;34:415-22; Juwle A et al. Med. Oncol. 2012 Dec;29:3272-81; Dodova RI et al. BMC Cancer. 2015 Jul;15:523; Labidi-Galy SI et al. Clin. Cancer Res. 2018 Jan;24(2):326-333; Jakimovska M et al. Breast Cancer Res. Treat. 2018 Apr;168(3):745-753; Fanale D et al. Cancers (Basel), 2020 Aug;12:; Wessman S et al. Cancers (Basel), 2021 Oct;13:). Of note, this alteration is also designated as 6079_6082delAGTT and 6079delAGTT in published literature. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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 | Jun 13, 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 reported in individuals affected with breast and ovarian cancer (PMID: 12955716, 18821011, 25186627, 26183948, 27153395, 27882536, 29487695, 29335924, 29470806, 30430080, 32438681, 32854451, 33471991, 34101484, 34680387, DOI: https://doi.org/10.1515/tjb-2019-0424, Leiden Open Variation Database DB-ID BRCA2_002145, Color internal data). 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. - |
Hereditary breast ovarian cancer syndrome Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 27, 2023 | This sequence change creates a premature translational stop signal (p.Ser1951Trpfs*11) 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 not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with breast and/or ovarian cancer (PMID: 18821011, 19805903, 22752604, 22970155, 26183948, 27882536, 29335924, 29487695). This variant is also known as 6079delAGTT. ClinVar contains an entry for this variant (Variation ID: 38001). For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Oct 28, 2022 | Variant summary: BRCA2 c.5851_5854delAGTT (p.Ser1951TrpfsX11) 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 was absent in 251070 control chromosomes. c.5851_5854delAGTT has been reported in the literature in multiple individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (examples: Kwong_2012, Juwle_2012, Diez_2003, etc). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. 12 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. 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 | - - |
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 | - - |
Gastric cancer Pathogenic:1
Pathogenic, no assertion criteria provided | research | Laboratory for Genotyping Development, RIKEN | Jul 01, 2021 | - - |
Familial cancer of breast Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Aug 05, 2022 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at