rs80359352
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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.2808_2811del(p.Ala938ProfsTer21) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000204 in 1,613,768 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 0.000013 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000021 ( 0 hom. )
Consequence
BRCA2
NM_000059.4 frameshift
NM_000059.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 1.84
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 13-32337160-TAAAC-T is Pathogenic according to our data. Variant chr13-32337160-TAAAC-T is described in ClinVar as [Pathogenic]. Clinvar id is 9322.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr13-32337160-TAAAC-T is described in Lovd as [Pathogenic]. Variant chr13-32337160-TAAAC-T is described in Lovd as [Pathogenic].
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| BRCA2 | NM_000059.4 | c.2808_2811del | p.Ala938ProfsTer21 | 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.2808_2811del | p.Ala938ProfsTer21 | frameshift_variant | 11/27 | 5 | NM_000059.4 | ENSP00000369497 | A2 |
Frequencies
GnomAD3 genomes 0.0000131 AC: 2AN: 152208Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.00000797 AC: 2AN: 250852Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135696
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GnomAD4 exome AF: 0.0000212 AC: 31AN: 1461560Hom.: 0 AF XY: 0.0000220 AC XY: 16AN XY: 727070
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GnomAD4 genome 0.0000131 AC: 2AN: 152208Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1AN XY: 74354
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:59Other:2
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
Breast-ovarian cancer, familial, susceptibility to, 2 Pathogenic:21
| Pathogenic, criteria provided, single submitter | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | Sep 21, 2015 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Department of Medical Genetics, Oslo University Hospital | Jul 01, 2015 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Michigan Medical Genetics Laboratories, University of Michigan | Apr 21, 2016 | - - |
| Pathogenic, no assertion criteria provided | literature only | OMIM | Dec 21, 1995 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Genologica Medica | Jan 01, 2017 | - - |
| 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 | case-control | Molecular Oncology, Hospital Universitario Central de Asturias (HUCA) | May 24, 2021 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Oct 09, 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 is also known as c.2806_2809del, 3034del4 and 3036del4 in the literature. This variant has been reported as a recurrent mutation worldwide in over 100 individuals affected with breast and/or ovarian cancer (PMID: 8665505, 11030418, 11158174, 12955716, 15024741, 21324516, 22006311, 21598239, 22970155, 23469205, 25476495, 26026974, 27257965, 28680148, 28692638, 29339979, 30287823) and a breast cancer case-control meta-analysis has reported this variant in 29/60437 cases and 6/53455 unaffected individuals (OR=4.275, 95%CI 1.775 to 10.298) (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA2_001211). This variant also has been reported in individuals affected with prostate cancer (PMID: 20736950, 29368341). This variant has been identified in 2/250852 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. - |
| Likely pathogenic, no assertion criteria provided | research | deCODE genetics, Amgen | Jul 21, 2023 | The variant NM_000059.4:c.2808_2811del (chr13:32337160) in BRCA2 was detected in 1 heterozygote out of 58K WGS Icelanders (MAF= 0,001%). This variant has been reported in ClinVar previously as pathogenic. Based on ACMG criteria (PVS1, PM2) this variant classifies as likely pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet | May 27, 2024 | PVS1; PM5_PTC_Strong - |
| Pathogenic, criteria provided, single submitter | clinical testing | Mendelics | May 28, 2019 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Jun 12, 2023 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine | May 22, 2018 | The c.2808_2811delACAA (p.Ala938Profs*21) frameshift variant in BRCA2 is predicted to introduce a premature translation termination codon. It has been reported in multiple unrelated patients with breast, ovarian or prostate cancer [PMID 8524414, 22144684, 21952622, 22006311, 21324516]. This variant is classified as pathogenic. - |
| Pathogenic, no assertion criteria provided | clinical testing | Sharing Clinical Reports Project (SCRP) | Jul 29, 2013 | - - |
| Pathogenic, criteria provided, single submitter | literature only | Counsyl | Jul 04, 2014 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Institute of Human Genetics, Medical University Innsbruck | Feb 11, 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 | Breast Cancer Information Core (BIC) (BRCA2) | Feb 20, 2013 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | BRCAlab, Lund University | Aug 26, 2022 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | MGZ Medical Genetics Center | May 04, 2022 | - - |
not provided Pathogenic:12
| Pathogenic, criteria provided, single submitter | clinical testing | Clinical Genetics Laboratory, Skane University Hospital Lund | Jun 19, 2023 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Mar 28, 2023 | PP5, PM2, PS4_moderate, PVS1 - |
| 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 | GeneKor MSA | Jan 01, 2020 | This sequence change deletes four bases from exon 11 of the BRCA2 mRNA (c.2808_2811delACAA), causing a frameshift after codon 938 and the creation of a premature translation stop signal 21 amino acid residues later, p.(Ala938Profs*21). This is expected to result in an absent or disrupted protein product. Truncating variants in BRCA2 are known to be pathogenic. This variant has been reported in the international literature in individuals affected with female breast cancer, male breast cancer, ovarian cancer, prostate cancer, and pancreatic cancer (PMID: 9585613, 21952622, 12955716, 23929434). This variant is also known as 2807del4, 3034del4, 3036del4, 3034delAAAC, 3036delACAA, and 3036_3039del4. The mutation database ClinVar contains entries for this variant (Variation ID: 9322). - |
| Pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Jun 22, 2022 | The BRCA2 c.2808_2811delACAA; Ala938ProfsTer21 variant (rs80359351) is reported in the literature in individuals affected with familial breast, ovarian, and prostate cancers (Edwards 2010, Kote-Jarai 2011, Walsh 2011, Wooster 1995, Zhang 2011), and it has been described as a founder variant in Western Europeans (Caputo 2012). This variant is reported as pathogenic by numerous sources in ClinVar (Variation ID: 9322) and is only observed on two alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. 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: Caputo S et al. Description and analysis of genetic variants in French hereditary breast and ovarian cancer families recorded in the UMD-BRCA1/BRCA2 databases. Nucleic Acids Res. 2012 Jan;40(Database issue):D992-1002. Edwards SM et al. Prostate cancer in BRCA2 germline mutation carriers is associated with poorer prognosis. Br J Cancer. 2010 Sep 7;103(6):918-24. Kote-Jarai Z et al. BRCA2 is a moderate penetrance gene contributing to young-onset prostate cancer: implications for genetic testing in prostate cancer patients. Br J Cancer. 2011 Oct 11;105(8):1230-4. Walsh T et al. Mutations in 12 genes for inherited ovarian, fallopian tube, and peritoneal carcinoma identified by massively parallel sequencing. Proc Natl Acad Sci U S A. 2011 Nov 1;108(44):18032-7. Wooster R et al. Identification of the breast cancer susceptibility gene BRCA2. Nature. 1995 Dec 21-28;378(6559):789-92. Zhang S et al. Frequencies of BRCA1 and BRCA2 mutations among 1,342 unselected patients with invasive ovarian cancer. Gynecol Oncol. 2011 May 1;121(2):353-7. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Aug 03, 2023 | The BRCA2 c.2808_2811del (p.Ala938Profs*21) 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 cancer (PMID: 12955716 (2003), 21598239 (2012), 28724667 (2017), 32101877 (2019), 33558524 (2021)), prostate cancer (PMID: 21952622 (2011)), and pancreatic cancer (PMID: 34399810 (2021)). The frequency of this variant in the general population, 0.000008 (2/250852 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 | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Feb 06, 2024 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Nov 27, 2023 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Nov 01, 2023 | BRCA2: PVS1, PM2, PS4:Moderate - |
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jan 27, 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 individuals with a personal or family history consistent with pathogenic variants in this gene as a recurrent variant in Western European and Hispanic populations (Wooster 1995, Spitzer 2000, Diez 2003, Salazar 2006, Janavicius 2010); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Not observed at a significant frequency in large population cohorts (Lek 2016); This variant is associated with the following publications: (PMID: 11158174, 8524414, 10699917, 12955716, 15876480, 23199084, 33054725, 32132887, 31980526, 32029870, 32854451, 32039725, 31263571, 29176636, 31447099, 32318955, 26689913, 29625052, 27741520, 31921681, 31957001, 31432501, 30199306, 31090900, 30093976, 30322717, 30702160, 30014164, 28111427, 30652428, 30078507, 30720863, 30217213, 29310832, 29161300, 29566657, 29907814, 29752822, 29084914, 29368341, 29339979, 28767289, 28680148, 26556299, 28724667, 28195393, 29335924, 27836010, 26576347, 25085752, 29128982, 28127413, 28985766, 27882536, 28008555, 27425403, 22970155, 12065746, 27286788, 26250392, 25371446, 22034289, 16758124, 25884701, 18702510, 12845657, 19383375, 26541979, 26010302, 20713847, 26740091, 25256238, 24916970, 26026974, 25476495, 24504028, 23929434, 22144684, 21952622, 22006311, 21324516, 20736950, 12142080, 29435039, 29470806, 28993434) - |
| Pathogenic, criteria provided, single submitter | clinical testing | Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden | Nov 03, 2021 | - - |
Hereditary breast ovarian cancer syndrome Pathogenic:6Other:1
| 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 | Department of Pathology and Molecular Medicine, Queen's University | Apr 20, 2017 | - - |
| Pathogenic, criteria provided, single submitter | research | Genetics Program, Instituto Nacional de Cancer | Nov 01, 2021 | - - |
| 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. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Aug 07, 2017 | Variant summary: The BRCA2 c.2808_2811delACAA (p.Ala938Profs) variant (legacy names: 3036del4 and 3036delACAA) results in a premature termination codon, predicted to cause a truncated or absent BRCA2 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. This variant is absent in 120732 control chromosomes from ExAC. This variant is known to be a one of the most common pathogenic variants in non-Ashkenazi Caucasians (Diez_2003, Caputo_2012, Hall_2009, Infante_2013). Several clinical diagnostic laboratories/reputable databases in ClinVar have classified this variant as pathogenic. Therefore, this variant is classified as pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jun 30, 2022 | The p.Ala938ProfsX21 variant in BRCA2 is a well-established pathogenic variant for hereditary breast and ovarian cancer (HBOC) and is one of the most common germline mutations in non-Ashkenazi Jewish individuals with breast cancer (Gao 2000 PMID: 11030417, Diez 2003 PMID: 12955716, Janavicius 2010 PMID: 23199084, Caputo 2012 PMID: 22144684, Kwong 2012 PMID: 22970155, Infante 2013 PMID: 23929434). This variant has also been identified in one male with prostate cancer and 5 males with breast cancer (Edwards 2010 PMID: 20736950, de Juan 2015 PMID: 26026974). Furthermore, this variant was identified in 2/113374 of European chromosomes by tby gnomAD (http://gnomad.broadinstitute.org). This variant was classified as Pathogenic on April 22, 2016 by the ClinGen-approved Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) expert panel (Variation ID 9322). The p.Ala938ProfsX21 variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 938 and leads to a premature termination codon 21 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 for HBOC. In summary, this variant meets our criteria to be classified as pathogenic for autosomal dominant HBOC. ACMG/AMP Criteria applied: PVS1, PS4, PM2. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 31, 2024 | This sequence change creates a premature translational stop signal (p.Ala938Profs*21) 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 (rs80359351, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with female breast cancer, male breast cancer, ovarian cancer, prostate cancer, and pancreatic cancer (PMID: 9585613, 12955716, 21952622, 23929434). This variant is also known as 2807del4, 3034del4, 3036del4, 3034delAAAC, 3036delACAA, and 3036_3039del4. ClinVar contains an entry for this variant (Variation ID: 9322). For these reasons, this variant has been classified as Pathogenic. - |
Familial cancer of breast Pathogenic:5
| Pathogenic, no assertion criteria provided | literature only | Center for Precision Medicine, Meizhou People's Hospital | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | Jul 24, 2024 | Criteria applied: PVS1,PM5_STR - |
| Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 27, 2024 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | KCCC/NGS Laboratory, Kuwait Cancer Control Center | May 30, 2023 | This sequence change creates a premature translational stop signal (p.Ala938Profs*21) 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 (rs80359351, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with female breast cancer, male breast cancer, ovarian cancer, prostate cancer, and pancreatic cancer (PMID: 9585613, 12955716, 21952622, 23929434). This variant is also known as 2807del4, 3034del4, 3036del4, 3034delAAAC, 3036delACAA, and 3036_3039del4. ClinVar contains an entry for this variant (Variation ID: 9322). For these reasons, this variant has been classified as Pathogenic. - |
| Pathogenic, no assertion criteria provided | research | Center of Medical Genetics and Primary Health Care | Apr 08, 2020 | ACMG Guidelines 2015 criteria The BRCA2 variant p.Ala938Profs is a known pathogenic variant in exon 11in a non-functional domain and in a mutation hotspot region of 23 pathogenic variants (PM1 Pathogenic Moderate). This frameshift variant truncates the protein domains after this residue which is an established disease mechanism in hereditary breast and ovarian cancer (PVS1 Pathogenic Very Strong). The allele frequency in GnomAD exomes is 0.00000797 which is less the threshold 0.0001 for recessive gene BRCA2, and this variant is not found in GnomAD genomes (PM2 Pathogenic Moderate). 1 pathogenic prediction from GERP versus no benign predictions supports its deleterious effect (PP3 Pathogenic Supporting). The variant has been classified as pathogenic by the ClinGen-approved ENIGMA expert panel (ClinVar SCV000282373.1) (PP5 Pathogenic Supporting). In this study this deleterious variant was found in two patients - a 29 and a 38-year-old female with unilateral breast cancer and a family history of cancer. Therefore, this variant was classified as a Pathogenic. - |
Breast and/or ovarian cancer Pathogenic:3
| Pathogenic, no assertion criteria provided | clinical testing | Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research | Mar 29, 2016 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | CZECANCA consortium | Jun 11, 2019 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Apr 25, 2023 | - - |
Hereditary cancer-predisposing syndrome Pathogenic:3
| Pathogenic, criteria provided, single submitter | curation | Sema4, Sema4 | Oct 12, 2021 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Dec 11, 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 is also known as c.2806_2809del, 3034del4 and 3036del4 in the literature. This variant has been reported as a recurrent mutation worldwide in over 100 individuals affected with breast and/or ovarian cancer (PMID: 8665505, 11030418, 11158174, 12955716, 15024741, 21324516, 22006311, 21598239, 22970155, 23469205, 25476495, 26026974, 27257965, 28680148, 28692638, 29339979, 30287823) and a breast cancer case-control meta-analysis has reported this variant in 29/60437 cases and 6/53455 unaffected individuals (OR=4.275, 95%CI 1.775 to 10.298) (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA2_001211). This variant also has been reported in individuals affected with prostate cancer (PMID: 20736950, 29368341). This variant has been identified in 2/250852 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 | Aug 02, 2023 | The c.2808_2811delACAA pathogenic mutation, located in coding exon 10 of the BRCA2 gene, results from a deletion of 4 nucleotides at nucleotide positions 2808 to 2811, causing a translational frameshift with a predicted alternate stop codon (p.A938Pfs*21). This mutation has been identified in multiple families with breast, ovarian, prostate, and other cancers (Diez O et al. Hum. Mutat. 2003 Oct;22:301-12; Edwards SM et al. Br. J. Cancer. 2010 Sep;103:918-24; Zhang S et al. Gynecol. Oncol. 2011 May;121:353-7; Torres D et al. Sci. Rep. 2017 Jul;7:4713; Alemar B et al. PLoS One, 2017 Nov;12:e0187630; Isaacsson Velho P et al. Prostate. 2018 Apr;78:401-407; Bertelsen B et al. NPJ Genom Med, 2019 Jun;4:13; Moradian MM et al. Hum Genome Var, 2021 Feb;8:9; Solano AR et al. Cancers (Basel), 2021 May;13) and has been reported as a Norwegian founder mutation (Heramb C et al. Hered Cancer Clin Pract. 2018 Jan;16:3). Of note, this alteration is also designated as 3036del4 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-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 neoplasm Pathogenic:2
| Pathogenic, criteria provided, single submitter | research | A.C.Camargo Cancer Center / LGBM, A.C.Camargo Cancer Center | - | - - |
| Pathogenic, criteria provided, single submitter | research | Laboratory of Molecular Diagnosis of Cancer, West China Hospital, Sichuan University | Nov 01, 2015 | - - |
BRCA2-related disorder Pathogenic:2
| Pathogenic, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Feb 16, 2024 | The BRCA2 c.2808_2811delACAA variant is predicted to result in a frameshift and premature protein termination (p.Ala938Profs*21). This variant has been repeatedly reported in patients and families with hereditary breast and ovarian cancer (see for example, Wooster et al. 1995. PubMed ID: 8524414; de Juan et al. 2015. PubMed ID: 26026974; Alemar et al. 2017. PubMed ID: 29161300; Heramb et al. 2018. PubMed ID: 29339979) as well as patients with prostate cancer (Edwards et al. 2010. PubMed ID: 20736950; Kote-Jarai et al. 2011. PubMed ID: 21952622). In ClinVar, it is reported as pathogenic by several laboratories, including the ENIGMA expert panel (https://www.ncbi.nlm.nih.gov/clinvar/variation/9322). This variant is reported in 0.0018% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Frameshift variants in BRCA2 are expected to be pathogenic. Taken together, this variant is interpreted as pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | DASA | Mar 05, 2022 | The c.2808_2811del;p.(Ala938Profs*21) is a null frameshift variant (NMD) in the BRCA2 gene and predicts alteration of the nonsense-mediate decay - NMD is present in a relevant exon to the transcript - PVS1. The variant was observed to have arisen de novo (paternity confirmed) in a patient with the disease and no family history (PMID:11158174) - PS2. This sequence change has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 9322; PMID: 21324516; 28680148; 26026974; 20104584) - PS4. This variant is not present in population databases (rs80359351- gnomAD; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2. In summary, the currently available evidence indicates that the variant is pathogenic. - |
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.Ala938Profs*21 variant was identified in 14 of 7122 proband chromosomes (frequency: 0.002) from individuals or families with breast, ovarian and prostate cancers, although it was not investigated in controls (Edwards 2010, Caux-Moncoutier 2011, Zhang 2011, van der Hout 2006). The variant was also identified in dbSNP (ID: rs80359351) "With Pathogenic allele", ClinVar (classified pathogenic and reviewed by an expert panel 2016, submitters: Invitae, Counsyl, Ambry Genetics, GeneDx and 29 other submitters), and UMD-LSDB (123X, classified as 5-causal). 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.2808_2811del variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 938 and leads to a premature stop codon 21 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 - Invitae Patient Insights Network | - | Variant interpreted as Pathogenic and reported on 11-12-2020 by Lab Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. - |
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