rs770318608
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong
The NM_000059.4(BRCA2):c.5576_5579del(p.Ile1859LysfsTer3) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000187 in 1,605,350 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. T1858T) 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 16 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
BRCA2 | NM_000059.4 | c.5576_5579del | p.Ile1859LysfsTer3 | frameshift_variant | 11/27 | ENST00000380152.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BRCA2 | ENST00000380152.8 | c.5576_5579del | p.Ile1859LysfsTer3 | frameshift_variant | 11/27 | 5 | NM_000059.4 | A2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000132 AC: 2AN: 151950Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000163 AC: 4AN: 244832Hom.: 0 AF XY: 0.0000151 AC XY: 2AN XY: 132392
GnomAD4 exome AF: 0.0000193 AC: 28AN: 1453400Hom.: 0 AF XY: 0.0000194 AC XY: 14AN XY: 722240
GnomAD4 genome ? AF: 0.0000132 AC: 2AN: 151950Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74194
ClinVar
Submissions by phenotype
not provided Pathogenic:12
Pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Dec 14, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Jul 31, 2024 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Nov 03, 2023 | The BRCA2 c.5576_5579delTTAA; p.Ile1859LysfsTer3 variant (rs80359520), also reported as 5802del4, 5803del4 and 5804del4, has been described in the literature in several individuals and families with breast and ovarian cancer (Foster 1996, George 2013, Schneegans 2012). This variant is reported as pathogenic by several sources in the ClinVar database (Variation ID: 37975) and is found in the general population with an overall allele frequency of 0.002% (4/244832 alleles) in the Genome Aggregation Database. 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 pathogenic. References: Foster KA et al. Somatic and germline mutations of the BRCA2 gene in sporadic ovarian cancer. Cancer Res. 1996 56(16):3622-5. George J et al. Nonequivalent gene expression and copy number alterations in high-grade serous ovarian cancers with BRCA1 and BRCA2 mutations. Clin Cancer Res. 2013 19(13):3474-84. Schneegans SM et al. Validation of three BRCA1/2 mutation-carrier probability models Myriad, BRCAPRO and BOADICEA in a population-based series of 183 German families. Fam Cancer. 2012 11(2):181-8. - |
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Nov 29, 2022 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | - | - - |
Pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jun 01, 2020 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Oct 12, 2020 | PVS1, PM2, PP5 - |
Pathogenic, criteria provided, single submitter | clinical testing | Clinical Genetics and Genomics, Karolinska University Hospital | Jun 12, 2014 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Dec 18, 2019 | 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 a multiple individuals with a personal or family history consistent with pathogenic variants in this gene (Ikeda 2001, Sugano 2008, Wang 2012, Kang 2015, Kim 2016, Eoh 2017, Pritzlaff 2017); Not observed at a significant frequency in large population cohorts (Lek 2016); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Also known as c.5574_5577delAATT or 5804del4; This variant is associated with the following publications: (PMID: 22160602, 23683081, 22798144, 28127413, 28541631, 30203341, 11149425, 8705994, 25863477, 23633455, 19016756, 22713736, 24578176, 26848529, 27914478, 28008555, 27633797, 24094589, 28166811, 29422015, 26681312, 28724667, 29348823, 29020732, 29360550, 21643751, 29752822, 29673794, 30287823, 28111427, 30720243, 30742731, 30702160, 30322717, 31143373, 30309222, 31666926, 32300630, 30291343, 29625052, 26689913, 30350268, 31447099, 29176636, 31214711) - |
Pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Aug 09, 2023 | The BRCA2 c.5576_5579del (p.Ile1859Lysfs*3) variant alters the translational reading frame of the BRCA2 mRNA and causes the premature termination of BRCA2 protein synthesis. This variant has been reported in the published literature in individuals and families with breast/ovarian cancer (PMIDs: 35918668 (2022), 34645131 (2022), 31143373 (2019), 30287823 (2018), 23683081 (2013), 23633455 (2013), 22713736 (2012), 22217648 (2012), 22160602 (2012), 20104584 (2010)), and biliary track cancer (PMIDs: 32918181 (2021), 31666926 (2019)). The frequency of this variant in the general population, 0.000016 (4/244832 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is consistent with pathogenicity. Based on the available information, this variant is classified as pathogenic. - |
Pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute | - | - - |
Breast-ovarian cancer, familial, susceptibility to, 2 Pathogenic:10
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, no assertion criteria provided | clinical testing | Sharing Clinical Reports Project (SCRP) | May 01, 2012 | - - |
Pathogenic, criteria provided, single submitter | research | Laan Lab, Human Genetics Research Group, University of Tartu | May 01, 2021 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Breast Cancer Information Core (BIC) (BRCA2) | May 29, 2002 | - - |
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, criteria provided, single submitter | clinical testing | Department of Medical Genetics, Oslo University Hospital | Jan 10, 2017 | - - |
Pathogenic, no assertion criteria provided | clinical testing | BRCAlab, Lund University | Aug 26, 2022 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Dec 13, 2023 | This variant deletes 4 nucleotides in exon 11 of the BRCA2 gene, creating a frameshift and premature translation stop signal. This variant as also known as 5802delTTAA, 5803delATTA, 5804_5808delTTAA, 5804del4 and c.5574_5577delAATT in the literature. This variant is expected to result in unstable variant messenger RNA, which is corroborated by an RNA analysis of allelic imbalance in expressed BRCA2 mRNA transcripts in a heterozygous variant carrier (PMID: 19471317). This variant has been reported in over 30 individuals affected with breast and ovarian cancer (PMID: 8705994, 11149425, 17262179, 20104584, 21233401, 22160602, 22713736, 22798144, 23479189, 23633455, 23683081, 24249303, 24578176, 24728189, 26848529). A Japanese breast cancer case-control study (PMID: 30287823) and a breast cancer case-control meta-analysis (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA2_001464) have reported this variant in 27/7104 cases and 3/23731 unaffected controls and 16/60450 cases and 7/53454 unaffected controls, respectively. This variant also has been reported in a prostate cancer case-control study in 11/7636 prostate cancer cases and 2/12366 unaffected controls (PMID: 31214711). This variant has been identified in 4/244832 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, criteria provided, single submitter | clinical testing | Genologica Medica | Jan 01, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Aug 25, 2015 | - - |
Hereditary breast ovarian cancer syndrome Pathogenic:5
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Apr 25, 2016 | Variant summary: The c.5576_5579delTTAA variant results in a premature termination codon, predicted to cause a truncated or absent BRCA2 protein, which is a commonly known mechanism for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (c.5585_5588delTGAA, c.5603_5606delACAG, c.5616_5620delAGTAA). The variant was observed in the large and broad cohorts of the ExAC project at an allele frequency of 0.003% which does not exceed the maximal expected allele frequency for a pathogenic variant in BRCA2 (0.075%). The variant has been cited in numerous affected individuals via the literature and databases, and has been classified by multiple reputable databases and clinical labs as "pathogenic". Taken together, this variant has been classified as 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 | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jul 15, 2021 | The p.Ile1859LysfsX3 variant in BRCA2 has been reported in >35 individuals with BRCA2-associated cancers (Saghir 2015 PMID:25777348, Kim 2016 PMID:26848529, Breast Cancer Information Core database (BIC): https://research.nhgri.nih.gov/bic/). It has also been identified in 0.002% (1/41368) African/African American chromosomes by gnomAD (http://gnomad.broadinstitute.org, v3.1). This frequency is low enough to be consistent with the frequency of hereditary breast and ovarian cancer (HBOC) in the general population. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 1859 and leads to a premature termination codon 3 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Heterozygous loss of function of the BRCA2 gene is an established disease mechanism in HBOC. Additionally, this variant was classified as pathogenic on April 22, 2016 by the ClinGen-approved ENIGMA expert panel (Variant ID 37975). In summary, this variant meets criteria to be classified as pathogenic for HBOC in an autosomal dominant manner. ACMG/AMP criteria applied: PS4, PM2_Supporting, PVS1. - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 28, 2024 | This sequence change creates a premature translational stop signal (p.Ile1859Lysfs*3) 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 (rs770318608, gnomAD 0.007%). This premature translational stop signal has been observed in individual(s) with breast and/or ovarian cancer (PMID: 8705994, 22160602, 22217648, 23633455, 23683081). This variant is also known as 5803delATTA, 5804del4, and 5574_5577delAATT. ClinVar contains an entry for this variant (Variation ID: 37975). For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, no assertion criteria provided | research | Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto | Jan 31, 2014 | - - |
Familial cancer of breast Pathogenic:3
Pathogenic, no assertion criteria provided | literature only | Center for Precision Medicine, Meizhou People's Hospital | - | - - |
Pathogenic, no assertion criteria provided | research | Department of Medical Laboratory Science, Faculty of Allied Health Sciences, University of Peradeniya | Oct 19, 2019 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 25, 2024 | - - |
Hereditary cancer-predisposing syndrome Pathogenic:3
Pathogenic, criteria provided, single submitter | curation | Sema4, Sema4 | Jul 12, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Mar 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 also known as 5802delTTAA, 5803delATTA, 5804_5808delTTAA, 5804del4 and c.5574_5577delAATT in the literature. This variant is expected to result in unstable variant messenger RNA, which is corroborated by an RNA analysis of allelic imbalance in expressed BRCA2 mRNA transcripts in a heterozygous variant carrier (PMID: 19471317). This variant has been reported in over 30 individuals affected with breast and ovarian cancer (PMID: 8705994, 11149425, 17262179, 20104584, 21233401, 22160602, 22713736, 22798144, 23479189, 23633455, 23683081, 24249303, 24578176, 24728189, 26848529). A Japanese breast cancer case-control study (PMID: 30287823) and a breast cancer case-control meta-analysis (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA2_001464) have reported this variant in 27/7104 cases and 3/23731 unaffected controls and 16/60450 cases and 7/53454 unaffected controls, respectively. This variant also has been reported in a prostate cancer case-control study in 11/7636 prostate cancer cases and 2/12366 unaffected controls (PMID: 31214711). This variant has been identified in 4/244832 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, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 17, 2022 | The c.5576_5579delTTAA pathogenic mutation, located in coding exon 10 of the BRCA2 gene, results from a deletion of 4 nucleotides at nucleotide positions 5576 to 5579, causing a translational frameshift with a predicted alternate stop codon (p.I1859Kfs*3). This mutation has been reported in numerous hereditary breast and ovarian cancer (HBOC) patients and families world-wide (Foster KA et al. Cancer Res. 1996 Aug;56:3622-5; Gonzalez-Angulo AM et al. Clin. Cancer Res. 2011 Mar;17:1082-9; Kim H et al. Breast Cancer Res. Treat. 2012 Aug;134:1315-26; Blay P et al. BMC Cancer. 2013 May;13:243; George J et al. Clin. Cancer Res. 2013 Jul;19:3474-84; Song H et al. Hum. Mol. Genet. 2014 Sep;23:4703-9; Kim YC et al. Oncotarget. 2016 Feb;7:9600-12; Susswein LR et al. Genet. Med. 2016 Aug;18:823-32; Maistro S et al. BMC Cancer. 2016 Dec;16:934; Zhao Q et al. J. Gynecol. Oncol. 2017 Jul;28:e39; Park JS et al. Cancer Res Treat, 2017 Oct;49:1012-1021; Sun J et al. Clin Cancer Res, 2017 Oct;23:6113-6119; Momozawa Y et al. Nat Commun, 2018 10;9:4083; Carter NJ et al. Gynecol Oncol, 2018 12;151:481-488; Liang Y et al. Med Sci Monit, 2018 Apr;24:2465-2475; Ryu JM et al. Breast Cancer Res Treat, 2019 Jan;173:385-395; Sunami K et al. Cancer Sci, 2019 Apr;110:1480-1490; Yoshida R et al. Oncotarget, 2019 May;10:3276-3284; Ueda M et al. Obstet Gynecol Int, 2019 May;2019:4365754; El Ansari FZ et al. BMC Cancer, 2020 Aug;20:747; Park CS et al. Asian J Surg, 2020 Oct;43:996-1001; Sirisena N et al. Breast Cancer Res, 2020 05;22:43; Shao D et al. Cancer Sci, 2020 Feb;111:647-657; Bang YJ et al. Cancer Res Treat, 2021 Oct). This mutation has also been identified in patients diagnosed with prostate and biliary tract cancer (Wardell CP et al. J Hepatol, 2018 05;68:959-969; Terashima T et al. Oncotarget, 2019 Oct;10:5949-5957; Momozawa Y et al. J Natl Cancer Inst, 2020 04;112:369-376; Power R et al. Fam Cancer, 2021 04;20:97-101). Of note, this alteration is also designated as c.5574_5577delAATT, 5803delATTA and 5804del4 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. - |
Breast and/or ovarian cancer Pathogenic:1
Pathogenic, no assertion criteria provided | clinical testing | Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research | Mar 10, 2009 | - - |
Gastric cancer Pathogenic:1
Pathogenic, no assertion criteria provided | research | Laboratory for Genotyping Development, RIKEN | Jul 01, 2021 | - - |
Malignant tumor of breast Pathogenic:1
Pathogenic, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The BRCA2 p.Ile1859Lysfs*3 variant was identified in 72 of 57,640 proband chromosomes (freq: 0.001) from individuals or families with breast or ovarian cancer and in 3 of 47,462 chromosomes (freq: 0.00006) from healthy individuals (Momozawa 2018, Bhaskaran 2019, George 2013, Foster 1996, Haeyoun 2012, Kokichi 2008, Jalkh 2012, Schneegans 2012, Jang 2012, Blay 2013). The variant was identified in dbSNP (rs1255151416) as “NA”, ClinVar (classified as pathogenic by Invitae, Ambry Genetics, Color, GeneDx and 17 other submitters), LOVD 3.0 (observed 35x) and UMD-LSDB (observed 26x). The variant was identified in control databases in 4 of 244,832 chromosomes at a frequency of 0.00002 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 1 of 15,994 chromosomes (freq: 0.0001), European in 2 of 111,564 chromosomes (freq: 0.00002), and East Asian in 1 of 18,154 chromosomes (freq: 0.00006); it was not observed in the Latino, Ashkenazi Jewish, South Asian, Finnish, or Other populations. The p.Ile1859Lysfs*3 variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 1859 and leads to a premature stop codon 3 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. - |
Hereditary breast ovarian cancer syndrome;C1838457:Fanconi anemia complementation group D1 Other:1
not provided, no classification provided | phenotyping only | GenomeConnect, ClinGen | - | GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at