rs80359485
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Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong
The NM_000059.4(BRCA2):c.5130_5133del(p.Tyr1710Ter) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000699 in 1,430,836 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 33)
Exomes 𝑓: 0.0000070 ( 0 hom. )
Consequence
BRCA2
NM_000059.4 frameshift
NM_000059.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 2.09
Genes affected
BRCA2 (HGNC:1101): (BRCA2 DNA repair associated) Inherited mutations in BRCA1 and this gene, BRCA2, confer increased lifetime risk of developing breast or ovarian cancer. Both BRCA1 and BRCA2 are involved in maintenance of genome stability, specifically the homologous recombination pathway for double-strand DNA repair. The largest exon in both genes is exon 11, which harbors the most important and frequent mutations in breast cancer patients. The BRCA2 gene was found on chromosome 13q12.3 in human. The BRCA2 protein contains several copies of a 70 aa motif called the BRC motif, and these motifs mediate binding to the RAD51 recombinase which functions in DNA repair. BRCA2 is considered a tumor suppressor gene, as tumors with BRCA2 mutations generally exhibit loss of heterozygosity (LOH) of the wild-type allele. [provided by RefSeq, May 2020]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 16 ACMG points.
PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PP5
Variant 13-32339482-TTATG-T is Pathogenic according to our data. Variant chr13-32339482-TTATG-T is described in ClinVar as [Pathogenic]. Clinvar id is 51775.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr13-32339482-TTATG-T is described in Lovd as [Pathogenic]. Variant chr13-32339482-TTATG-T is described in Lovd as [Pathogenic].
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| BRCA2 | NM_000059.4 | c.5130_5133del | p.Tyr1710Ter | frameshift_variant | 11/27 | ENST00000380152.8 | NP_000050.3 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| BRCA2 | ENST00000380152.8 | c.5130_5133del | p.Tyr1710Ter | frameshift_variant | 11/27 | 5 | NM_000059.4 | ENSP00000369497 | A2 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
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33
GnomAD3 exomes AF: 0.00000441 AC: 1AN: 226864Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 122978
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GnomAD4 exome AF: 0.00000699 AC: 10AN: 1430836Hom.: 0 AF XY: 0.00000704 AC XY: 5AN XY: 709840
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:23
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
Breast-ovarian cancer, familial, susceptibility to, 2 Pathogenic:7
| Pathogenic, no assertion criteria provided | clinical testing | Sharing Clinical Reports Project (SCRP) | Sep 13, 2010 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Apr 10, 2023 | This variant deletes 4 nucleotides in exon 11 of the BRCA2 gene, creating a frameshift and premature translation stop signal. This variant is also known as c.5129_5132delATGT, 5358delTGTA and 5357del4 in the literature. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in at least 15 individuals affected with breast and/or ovarian cancer (PMID: 9012404, 17688236, 19656415, 21720365, 22034289, 23479189, 24249303, 25682074, 26845104, 28008555, 28294317, 33471991; Leiden Open Variation Database DB-ID BRCA2_001903). This variant has been identified in 1/226864 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, 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 | Mar 02, 2020 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Mar 08, 2016 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Breast Cancer Information Core (BIC) (BRCA2) | Jan 07, 2014 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge | Oct 02, 2015 | - - |
not provided Pathogenic:5
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jul 16, 2021 | Nonsense 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; Not observed at a significant frequency in large population cohorts (Lek 2016); Truncating variants in this gene are considered pathogenic by a well-established consortium and/or database; Also known as 5358_5361delTGTA, 5358delTGTA, or 5358del4; This variant is associated with the following publications: (PMID: 29176636, 31447099, 26689913, 29625052, 31721781, 17688236, 30322717, 30702160, 30720243, 27989354, 28831036, 28127413, 26845104, 28008555, 24249303, 26586665, 26187060, 25682074, 19656415, 23479189, 9012404, 22430266, 18465347, 20665887, 22034289, 31060517) - |
| Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Dec 15, 2023 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Feb 16, 2023 | This nonsense variant causes the premature termination of BRCA2 protein synthesis. The frequency of this variant in the general population, 0.0000044 (1/226864 chromosomes, http://gnomad.broadinstitute.org), is consistent with pathogenicity. In the published literature, the variant has been reported in individuals with a personal or family history of breast and/or ovarian cancer (PMIDs: 33471991 (2021) see also LOVD (https://databases.lovd.nl/shared/variants/BRCA2), 32885271 (2020), 31825140 (2020), 30130155 (2018), 30322717 (2018), 29625052 (2018), 28888541 (2017), 26689913 (2015), 28008555 (2017), 26845104 (2016), 26586665 (2015)), prostate cancer (PMIDs: 33804961 (2021), 27989354 (2017)), pancreatic cancer (PMID: 32980694 (2020)), and healthy individuals (PMIDs: 33471991 (2021) see also LOVD (https://databases.lovd.nl/shared/variants/BRCA2), 33804961 (2021), 32719484 (2020), 31447099 (2019)). Based on the available information, this variant is classified as pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | GeneKor MSA | Jan 01, 2020 | This is a deletion of 4 base pairs, which results in frameshift and creation of a new stop codon at amino acid residue 1710 of the BRCA2 gene. This is expected to result in an absent or disrupted protein product. Truncating variants in the BRCA2 gene are known to be pathogenic. This variant has been described in mutation databases as 5358_5361delTGTA, 5358delTGTA, or 5358del4. The mutation database ClinVar contains an entry for this variant (Variation ID: 51775). - |
| Pathogenic, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The BRCA2 p.Tyr1710* variant was identified in 22 of 48352 proband chromosomes (frequency: 0.0005) from individuals or families with hereditary breast and ovarian cancer (Rebbeck 2018, Soumittra 2009, Wong-Brown 2015, Bhaskaran 2019, Friedman 1997, de Juan Jimenez 2013, Shirts 2016, Fackenthal 2012, Finkelman 2012, Thomassen 2008, Ramus 2007). The variant was identified in dbSNP (rs760558178) as “NA”, ClinVar (classified as pathogenic by Invitae, Ambry Genetics, Color, GeneDx and 11 other submitters), LOVD 3.0 (observed 18x) and UMD-LSDB (observed 10x). The variant was identified in control databases in 1 of 226,864 chromosomes at a frequency of 0.000004 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the African population in 1 of 15268 chromosomes (freq: 0.00007), while it was not observed in the Latino, Ashkenazi Jewish, East Asian, Finnish, European, Other or South Asian populations. The c.5130_5133del variant leads to a premature stop codon at position 1710, which is predicted to lead to 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. - |
Hereditary breast ovarian cancer syndrome Pathogenic:5
| Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Apr 27, 2021 | The p.Tyr1710X variant in BRCA2 has been reported in >15 individuals with BRCA2-related cancers (Friedman 1997 PMID: 9012404, Soumittra 2009 PMID: 19656415, de Juan Jiménez 2013 PMID: 23479189, Wong-Brown 2015 PMID: 25682074, Maxwell 2017 PMID: 28831036, Na 2017 PMID: 27989354, Pritzlaff 2017 PMID: 28008555, breast cancer information core (BIC) database: https://research.nhgri.nih.gov/bic/). It has also been identified in 0.0065% (1/15268) of African chromosomes by gnomAD (http://gnomad.broadinstitute.org). This frequency is low enough to be consistent with the frequency of hereditary breast and ovarian cancer (HBOC) in the general population. This nonsense is a result of a deletion of 4 bases (c.5130_5133delTGTA), which creates a premature termination codon at amino acid position 1710. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the BRCA2 gene is an established disease mechanism in autosomal dominant HBOC. Additionally, this variant was classified as pathogenic on Apr 22, 2016 by the ClinGen-approved ENIGMA expert panel (Variation ID: 51775). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant HBOC. ACMG/AMP Criteria applied: PS4, PM2_Supporting, PVS1. - |
| 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 | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Apr 06, 2018 | Variant summary: BRCA2 c.5130_5133delTGTA (p.Tyr1710X) 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. The variant allele was found at a frequency of 4.5e-06 in 222984 control chromosomes. c.5130_5133delTGTA has been reported in the literature in multiple individuals affected with Hereditary Breast and Ovarian Cancer (e.g. Friedman 1997, Ramus 2007, Thomassen 2008, Soumittra 2009, Fackenthal 2012). 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. 11 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, criteria provided, single submitter | clinical testing | Department of Pathology and Molecular Medicine, Queen's University | Apr 20, 2017 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Dec 27, 2023 | This sequence change creates a premature translational stop signal (p.Tyr1710*) 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 (rs760558178, gnomAD 0.007%). This premature translational stop signal has been observed in individual(s) with breast cancer (PMID: 9012404, 19656415, 23479189, 25682074, 26586665, 26845104). This variant is also known as 5358del4 and p.Tyr1693X. ClinVar contains an entry for this variant (Variation ID: 51775). 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 | Jun 28, 2021 | The c.5130_5133delTGTA pathogenic mutation (also known as p.Y1710*), located in coding exon 10 of the BRCA2 gene, results from a deletion of 4 nucleotides at nucleotide positions 5130 to 5133. This changes the amino acid from a tyrosine to a stop codon within coding exon 10. This alteration has been reported in numerous breast and/or ovarian cancer cohorts (Friedman LS et al. Am. J. Hum. Genet. 1997 Feb;60:313-9; Soumittra N et al. Hered. Cancer Clin. Pract. 2009 Aug;7:13; de Juan Jiménez I et al. Fam. Cancer. 2013 Dec;12:767-77; Nakamura S et al. Breast Cancer. 2015 Sep;22:462-8; Wong-Brown MW et al. Breast Cancer Res. Treat. 2015 Feb;150:71-80; Pritzlaff M et al. Breast Cancer Res. Treat. 2017 Feb;161:575-586; Carter NJ et al. Gynecol Oncol, 2018 12;151:481-488; Dorling et al. N Engl J Med. 2021 02;384:428-439). Of note, this alteration is also designated as 5358del4 and c.5129_5132delATGT 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 16, 2024 | This variant deletes 4 nucleotides in exon 11 of the BRCA2 gene, creating a frameshift and premature translation stop signal. This variant is also known as c.5129_5132delATGT, 5358delTGTA and 5357del4 in the literature. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in at least 15 individuals affected with breast and/or ovarian cancer (PMID: 9012404, 17688236, 19656415, 21720365, 22034289, 23479189, 24249303, 25682074, 26845104, 28008555, 28294317, 33471991; Leiden Open Variation Database DB-ID BRCA2_001903). This variant has been identified in 1/226864 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. - |
Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | University of Washington Department of Laboratory Medicine, University of Washington | Nov 20, 2015 | - - |
BRCA2-related disorder Pathogenic:1
| Pathogenic, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Mar 22, 2024 | The BRCA2 c.5130_5133delTGTA variant is predicted to result in premature protein termination (p.Tyr1710*). This variant has been reported in individuals with breast and ovarian cancer (male patient, Friedman et al. 1997. PubMed ID: 9012404; Table S1, Carter et al. 2018. PubMed ID: 30322717; de Juan Jiménez et al. 2013. PubMed ID: 23479189). This variant is reported in 0.0065% of alleles in individuals of African descent in gnomAD. It is interpreted as pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/51775/). Nonsense variants in BRCA2 are expected to be pathogenic. This variant is interpreted as pathogenic. - |
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 | Mar 25, 2024 | - - |
Computational scores
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