13-32329467-CTG-C
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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.658_659del(p.Val220IlefsTer4) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000257 in 1,597,642 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: 𝑓 0.000046 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000024 ( 0 hom. )
Consequence
BRCA2
NM_000059.4 frameshift
NM_000059.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 1.39
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 13-32329467-CTG-C is Pathogenic according to our data. Variant chr13-32329467-CTG-C is described in ClinVar as [Pathogenic]. Clinvar id is 9342.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr13-32329467-CTG-C is described in Lovd as [Pathogenic]. Variant chr13-32329467-CTG-C is described in Lovd as [Pathogenic].
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| BRCA2 | NM_000059.4 | c.658_659del | p.Val220IlefsTer4 | frameshift_variant | 8/27 | ENST00000380152.8 | NP_000050.3 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| BRCA2 | ENST00000380152.8 | c.658_659del | p.Val220IlefsTer4 | frameshift_variant | 8/27 | 5 | NM_000059.4 | ENSP00000369497 | A2 |
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GnomAD3 genomes 0.0000460 AC: 7AN: 152134Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000449 AC: 11AN: 245032Hom.: 0 AF XY: 0.0000302 AC XY: 4AN XY: 132466
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:50Other:1
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
Breast-ovarian cancer, familial, susceptibility to, 2 Pathogenic:14
| Pathogenic, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Jan 08, 2024 | The c.658_659delGT (p.Val220Ilefs*4) variant in the BRCA2 gene is located on the exon 8 and is predicted to cause reading frame shift that introduces a premature translation termination codon (p.Val220Ilefs*4), resulting in an absent or disrupted protein product. Loss-of-function variants of BRCA2 are known to be pathogenic (PMID: 11897832). This c.658_659delGT variant was reported in more than 10 unrelated individuals with ovarian/breast cancer (PMID: 33478551, 34097676, 33670479, 32571290, 32824581, 22923021). It is one of the most frequently observed BRCA2 variants in North America and Lithuania, and more than 20 families were reported with the variant and disease (PMID: 29446198). This variant is reported in ClinVar as pathogenic (ID: 9342) and reviewed by the expert panel. The variant is rare in the general population according to gnomAD (13/276414). Therefore, the c.658_659delGT (p.Val220Ilefs*4) variant of BRCA2 has been classified as pathogenic. - |
| Pathogenic, criteria provided, single submitter | literature only | Counsyl | Feb 04, 2015 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, Clinical Exome/Genome Diagnostics Group, University Hospital Bonn | Oct 29, 2021 | Incidental finding in clinical exome sequencing. PVS1, PS4, PS5 - |
| Pathogenic, no assertion criteria provided | clinical testing | Sharing Clinical Reports Project (SCRP) | Jan 04, 2014 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | Dec 29, 2023 | Criteria applied: PVS1,PM5_STR - |
| Pathogenic, criteria provided, single submitter | clinical testing | Michigan Medical Genetics Laboratories, University of Michigan | Nov 03, 2014 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | BRCAlab, Lund University | Aug 26, 2022 | - - |
| 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 | Oct 06, 2015 | - - |
| 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 | Breast Cancer Information Core (BIC) (BRCA2) | May 29, 2002 | - - |
| Pathogenic, criteria provided, single submitter | research | HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology | Jul 10, 2014 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | Sep 21, 2015 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
not provided Pathogenic:10
| Pathogenic, criteria provided, single submitter | clinical testing | Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen | Oct 23, 2020 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Sep 19, 2022 | The BRCA2 c.658_659delGT (p.Val220IlefsTer4) variant results in the deletion of two nucleotides at position c.658-659, causing a shift in the protein reading frame that is predicted to result in premature termination of the protein. Loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay is expected. Across a selection of the available literature, the c.658_659delGT variant, also referred to as c.886delGT, has been identified in a heterozygous state in at least eight individuals with breast cancer and one individual with ovarian cancer (PMID: 9667259; PMID: 23767878; PMID: 24504028; PMID: 27153395). The variant has also been observed in a compound heterozygous state in at least seven individuals with Fanconi anemia (PMID: 14670928; PMID: 26064523). The highest frequency of this allele in the Genome Aggregation Database is 0.000126 in the African/African-American population. Based on the available evidence the c.658_659delGT (p.Val220IlefsTer4) variant is classified as pathogenic for hereditary breast and ovarian cancer. - |
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Mar 16, 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 the heterozygous state in individuals from hereditary breast and ovarian cancer families (Frank 1998, Jakubowska 2003, Machado 2007, Berzina 2013, Cunningham 2014, de Juan 2015); Observed in the compound heterozygous state with a second pathogenic BRCA2 variant in patients with Fanconi anemia (Alter 2007, Miele 2015); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Also known as 886delGT; This variant is associated with the following publications: (PMID: 9667259, 14647210, 15689453, 27836010, 26681312, 30128899, 17513806, 23767878, 24504028, 26026974, 16825431, 26064523, 26779294, 24528374, 26843898, 22535016, 27376475, 27153395, 26657402, 27831900, 14559878, 14670928, 28724667, 28324225, 28166811, 22009639, 29339979, 29753700, 29492181, 30078507, 29310832, 30350268, 30630528, 30122538, 30720243, 29790872, 29575201, 30093976, 31411802, 31396961, 31263054, 31957001, 27741520, 29625052, 26689913, 32318955, 31447099, 31980526, 31948886, 34008015, 32467295, 31589614, 32341426, 31825140, 32719484, 30787465) - |
| Pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Mar 02, 2023 | This variant alters the translational reading frame of the BRCA2 mRNA and causes the premature termination of BRCA2 protein synthesis. In the published literature, this variant has been reported in individuals with breast and/or ovarian cancer (PMIDs: 35220195 (2022), 33478551 (2021), 32438681 (2020), 32098980 (2020), 32341426 (2020), 32318955 (2020), 31980526 (2020), 31957001 (2020), 31411802 (2019), 31263054 (2019), 30350268 (2018), 30287823 (2018), 29492181 (2018)). Additionally, the variant has been reported in individuals with prostate cancer (PMIDs: 31948886 (2020), 32875559 (2020)), colorectal cancer (PMID: 26681312 (2015)), mesothelioma (PMID: 34008015 (2021), and esophageal squamous cell carcinoma (PMID: 31396961 (2020)). The variant has occurred with an additional pathogenic BRCA2 variant in children with Fanconi Anemia, Wilm's tumor, and/or medulloblastoma (PMIDs: 29753700 (2018), 26657402 (2016), 26064523 (2015), 16825431 (2007), 15689453 (2005), 14670928 (2004)). The frequency of this variant in the general population, 0.00013 (3/23770 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is consistent with pathogenicity. 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 | Aug 10, 2023 | The BRCA2 c.658_659delGT; p.Val220IlefsTer4 variant (rs80359604), also known as 886delGT, is reported in the literature in multiple individuals affected with hereditary breast and ovarian cancer syndrome (Cunningham 2014, de Juan 2015, Frank 1998, Heramb 2018), and in patients with Fanconi anemia when found in-trans with another pathogenic variant (Hirsch 2004, Svojgr 2016). This variant is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 9342), and is found in the African/African American population with an allele frequency of 0.013% (3/23,770 alleles) in the Genome Aggregation Database. This variant causes a frameshift by deleting 2 nucleotides, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, the p.Val220IlefsTer4 variant is considered to be pathogenic. References: Cunningham J et al. Clinical characteristics of ovarian cancer classified by BRCA1, BRCA2, and RAD51C status. Sci Rep. 2014 4:4026. PMID: 24504028. de Juan I et al. BRCA1 and BRCA2 mutations in males with familial breast and ovarian cancer syndrome. Results of a Spanish multicenter study. Fam Cancer. 2015 14(4):505-13. PMID: 26026974. Frank T et al. Sequence analysis of BRCA1 and BRCA2: correlation of mutations with family history and ovarian cancer risk. J Clin Oncol. 1998 16(7):2417-25. PMID: 9667259. Heramb C et al. BRCA1 and BRCA2 mutation spectrum - an update on mutation distribution in a large cancer genetics clinic in Norway. Hered Cancer Clin Pract. 2018 Jan 10;16:3. PMID: 29339979. Hirsch B et al. Association of biallelic BRCA2/FANCD1 mutations with spontaneous chromosomal instability and solid tumors of childhood. Blood. 2004 103(7):2554-9. PMID: 14670928. Svojgr K et al. Fanconi anemia with biallelic FANCD1/BRCA2 mutations - Case report of a family with three affected children. Eur J Med Genet. 2016 59(3):152-7. PMID: 26657402. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Clinical Genetics and Genomics, Karolinska University Hospital | Nov 18, 2015 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Clinical Genetics Laboratory, Skane University Hospital Lund | May 27, 2022 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Oct 25, 2019 | PVS1, PM2, PP5 - |
| Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Dec 01, 2023 | BRCA2: PVS1, PS3:Moderate, PS4:Supporting - |
| Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Mar 03, 2023 | - - |
Hereditary breast ovarian cancer syndrome Pathogenic:4
| Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Nov 23, 2022 | The p.Val220IlefsX4 variant in BRCA2 has been identified in >50 individuals with BRCA2-associated cancers (Frank 1998 PMID:9667259, Berzina 2013 PMID:23767878, Breast Cancer Information Core (BIC) database: https://research.nhgri.nih.gov/bic/) and in 3 compound heterozygous individuals with Fanconi anemia (Offit 2003 PMID:14559878, Hirsch 2004 PMID:14670928, Reid 2005 PMID:15689453). It has also been identified in 0.012% (5/41438) of African/African American chromosomes and in 0.003% (2/68004) of European 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 220 and leads to a premature termination codon 4 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 autosomal dominant hereditary breast and ovarian cancer (HBOC). Additionally, this variant was classified as pathogenic on Apr 22, 2016 by the ClinGen-approved ENIGMA expert panel (Variation ID 9342). 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 | Labcorp Genetics (formerly Invitae), Labcorp | Jan 29, 2024 | This sequence change creates a premature translational stop signal (p.Val220Ilefs*4) 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 (rs768580992, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with hereditary breast and ovarian cancer (PMID: 9667259, 22923021, 23767878, 24504028, 26657402). This variant is also known as 886delGT. ClinVar contains an entry for this variant (Variation ID: 9342). 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 | Apr 18, 2016 | Variant summary: The c.658_659delGT 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.755_758delACAG, p.Asp252fsX24; c.771_775delTCAAA, p.Asn257fsX17; c.778_779delGA, p.Glu260fsX15). The variant was observed in the large and broad cohorts of the ExAC project at an allele frequency of 0.006% which does not exceed the maximal expected allele frequency for a pathogenic variant in BRCA2 (0.075%). The variant has been reported in numerous affected individuals in the literature, including 2 siblings affected with Fanconi anemia who also carried a second pathogenic BRCA2 variant (Svojgr_2016). Mutliple reputable clinical labs have classified the variant as "Pathogenic". Taken together, this variant is 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, criteria provided, single submitter | clinical testing | Institute of Human Genetics, Clinical Exome/Genome Diagnostics Group, University Hospital Bonn | Oct 29, 2021 | Incidental finding in clinical exome sequencing. PVS1, PS4, PS5 - |
| Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Feb 26, 2024 | - - |
| Pathogenic, no assertion criteria provided | literature only | Center for Precision Medicine, Meizhou People's Hospital | - | - - |
Hereditary cancer-predisposing syndrome Pathogenic:3
| Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 17, 2021 | The c.658_659delGT pathogenic mutation, located in coding exon 7 of the BRCA2 gene, results from a deletion of 2 nucleotides at positions 658 to 659, causing a translational frameshift with a predicted alternate stop codon (p.V220Ifs*4). This mutation has been described in numerous HBOC families (Frank TS et al. J. Clin. Oncol. 1998 Jul;16:2417-25; Berzina D et al. BMC Med. Genet. 2013;14:61; Meisel C et al. Arch. Gynecol. Obstet. 2017 May;295:1227-1238). This mutation has also been observed in Fanconi anemia group D1 patients and was associated with brain tumors (medulloblastomas and glioblastomas) and Wilms tumor in these patients (Alter BP et al. J. Med. Genet. 2007 Jan;44:1-9; Miele E et al. Biomark Res. 2015;3:13). Of note, this alteration is also designated as 886delGT in some 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 classified as a disease-causing mutation. However, because this variant is identified in one or more patients with Fanconi Anemia it may be hypomorphic and thus, carriers of this variant and their families may present with reduced risks, and not with the typical clinical characteristics of a high-risk pathogenic BRCA2 alteration. As risk estimates are unknown at this time, clinical correlation is advised. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Apr 11, 2023 | This variant deletes 2 nucleotides in exon 8 of the BRCA2 gene, creating a frameshift and premature translation stop signal. This variant is also known as 886delGT in the literature. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in multiple individuals affected with breast and ovarian cancer (PMID: 9667259, 22923021, 23767878, 24504028, 27153395, 28324225, 28724667, 30287823). It has also been observed in compound heterozygous state with a pathogenic variant in two individuals affected with Fanconi anemia (PMID: 16825431). This variant has been identified in 13/276414 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 | curation | Sema4, Sema4 | Feb 10, 2021 | - - |
Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:2
| Pathogenic, criteria provided, single submitter | clinical testing | Department of Molecular Diagnostics, Institute of Oncology Ljubljana | Apr 02, 2020 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | University of Washington Department of Laboratory Medicine, University of Washington | Nov 20, 2015 | - - |
Breast and/or ovarian cancer Pathogenic:2
| Pathogenic, no assertion criteria provided | case-control;clinical testing | CZECANCA consortium | Jun 11, 2019 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research | Dec 04, 2016 | - - |
Medulloblastoma Pathogenic:2
| Pathogenic, no assertion criteria provided | literature only | OMIM | Jan 01, 2007 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, Clinical Exome/Genome Diagnostics Group, University Hospital Bonn | Oct 29, 2021 | Incidental finding in clinical exome sequencing. PVS1, PS4, PS5 - |
Wilms tumor 1 Pathogenic:2
| Pathogenic, no assertion criteria provided | literature only | OMIM | Jan 01, 2007 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, Clinical Exome/Genome Diagnostics Group, University Hospital Bonn | Oct 29, 2021 | Incidental finding in clinical exome sequencing. PVS1, PS4, PS5 - |
BRCA2-related disorder Pathogenic:2
| Pathogenic, criteria provided, single submitter | clinical testing | Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego | - | This frameshifting variant in exon 8 of 28 introduces a premature stop codon and is therefore predicted to result in loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay (NMD). This variant has been previously reported in individuals with breast and ovarian cancer (PMID: 22923021, 23767878, 28324225). This variant has also been reported as a compound heterozygous change in patients with Fanconi anemia (PMID: 16825431). Loss-of-function variation in BRCA2 is an established mechanism of disease (PMID: 20104584). The c.658_659del (p.Val220IlefsTer4) variant is present in the heterozygous state in the gnomAD population database at a frequency of 0.005% (13/276414) and thus is presumed to be rare. Based on the available evidence, the c.658_659del (p.Val220IlefsTer4) variant is classified as Pathogenic. - |
| Pathogenic, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Jun 25, 2024 | The BRCA2 c.658_659delGT variant is predicted to result in a frameshift and premature protein termination (p.Val220Ilefs*4). This variant is alternatively described as c.658delGT, c.886delGT or c.886_887delGT. This variant has been observed in individuals with personal and family histories of breast and/or ovarian cancer (Novakovic et al. 2012. PubMed ID: 22923021; Berzina et al. 2013. PubMed ID: 23767878; Tung et al. 2016. PubMed ID: 26976419), Fanconi anemia (group D1), and other types of malignancies, including brain tumors (Offit et al. 2003. PubMed ID: 14559878; Reid et al. 2005. PubMed ID: 15689453; Alter et al. 2006, PubMed ID: 16825431). This variant, in combination with another variant in the same or a different gene, has also been reported in individuals with multiple malignancies including colorectal cancer (Heidemann et al. 2012. PubMed ID: 22535016; Degrolard-Courcet et al. 2014, PubMed ID: 24301060). This variant is reported in 0.013% of alleles in individuals of African descent in gnomAD. In ClinVar, it has been classified as pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/9342). Frameshift variants in BRCA2 are expected to be pathogenic. This variant is interpreted as pathogenic. - |
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 29, 2021 | - - |
Fanconi anemia complementation group D1 Pathogenic:1
| Pathogenic, no assertion criteria provided | literature only | OMIM | Jan 01, 2007 | - - |
Gastric cancer Pathogenic:1
| Pathogenic, no assertion criteria provided | research | Laboratory for Genotyping Development, RIKEN | Jul 01, 2021 | - - |
Uterine corpus cancer Pathogenic:1
| Pathogenic, no assertion criteria provided | clinical testing | CZECANCA consortium | Feb 21, 2023 | - - |
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.Val220Ilefs*4 variant was identified in 19 of 19400 proband chromosomes (frequency: 0.001) from individuals or families with breast or ovarian cancer (Bayraktar 2012, Berzina 2013, Frank 1998, Heidemann 2012, Janavicius 2014, Novakovic 2012). The variant was also identified in the case study in two siblings with Fanconi anemia with biallelic FANCD1/BRCA2 mutations (Svojgr 2016). The variant was also identified in dbSNP (ID: rs80359604) as “With Pathogenic allele”, ClinVar (classified as pathogenic by Invitae, Ambry Genetics, GeneDx and seventeen other submitters), LOVD 3.0 (58X as pathogenic), and in UMD-LSDB (30X as causal). This mutation was found at a high frequency in the Lithuanian population and could represent a Baltic founder mutation (Janavicius 2014).The variant was not identified in the following control databases: the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). The c.658_659del variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 220 and leads to a premature stop codon at position 223. 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 BRCA associated cancers 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. - |
Malignant tumor of prostate Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, Clinical Exome/Genome Diagnostics Group, University Hospital Bonn | Oct 29, 2021 | Incidental finding in clinical exome sequencing. PVS1, PS4, PS5 - |
Glioma susceptibility 3 Other:1
| risk factor, no assertion criteria provided | literature only | OMIM | Jan 01, 2007 | - - |
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