chr13-32340756-ATAACT-A
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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.6405_6409del(p.Asn2135LysfsTer3) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000199 in 1,605,012 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: 33)
Exomes 𝑓: 0.000021 ( 0 hom. )
Consequence
BRCA2
NM_000059.4 frameshift
NM_000059.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 0.959
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 13-32340756-ATAACT-A is Pathogenic according to our data. Variant chr13-32340756-ATAACT-A is described in ClinVar as [Pathogenic]. Clinvar id is 38043.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr13-32340756-ATAACT-A is described in Lovd as [Pathogenic]. Variant chr13-32340756-ATAACT-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| BRCA2 | NM_000059.4 | c.6405_6409del | p.Asn2135LysfsTer3 | 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.6405_6409del | p.Asn2135LysfsTer3 | frameshift_variant | 11/27 | 5 | NM_000059.4 | ENSP00000369497 | A2 |
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GnomAD3 genomes 0.0000131 AC: 2AN: 152224Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.00000416 AC: 1AN: 240630Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 130596
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GnomAD4 exome AF: 0.0000207 AC: 30AN: 1452788Hom.: 0 AF XY: 0.0000208 AC XY: 15AN XY: 722594
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GnomAD4 genome 0.0000131 AC: 2AN: 152224Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74382
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:45
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
Breast-ovarian cancer, familial, susceptibility to, 2 Pathogenic:15
| Pathogenic, no assertion criteria provided | clinical testing | Sharing Clinical Reports Project (SCRP) | Jul 02, 2012 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Mendelics | May 28, 2019 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | May 31, 2017 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Zotz-Klimas Genetics Lab, MVZ Zotz Klimas | Nov 24, 2023 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Jul 05, 2017 | - - |
| Pathogenic, criteria provided, single submitter | research | Institute of Genomics, University of Tartu | - | - - |
| Pathogenic, no assertion criteria provided | clinical testing | BRCAlab, Lund University | Mar 02, 2020 | - - |
| Pathogenic, no assertion criteria provided | case-control | Molecular Oncology, Hospital Universitario Central de Asturias (HUCA) | May 24, 2021 | - - |
| 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) | May 29, 2002 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The BRCA2 p.Asn2135Lysfs*3 variant was identified in 12 of 11758 proband chromosomes (frequency: 0.001) from individuals or families with breast, ovarian, and prostate cancer (Borg 2010, de Juan 2015, Gayther 1997, Kote-Jarai 2011, Zhang 2011). The variant was also identified in dbSNP (ID: rs80359584) as “With Pathogenic allele”, in ClinVar (classified as pathogenic by Color Genomics, Invitae, GeneDx, Ambry Genetics, SCRP, BIC, and 11 clinical laboratories), COGR, LOVD 3.0, UMD-LSDB (67x causal), BIC Database (13x clinically important), and in ARUP Laboratories (definitely pathogenic). The variant was not identified in Cosmic, or the Zhejiang University Database, the 1000 Genomes Project, the NHLBI GO Exome Sequencing Project, the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). The c.6405_6409del variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 2135 and leads to a premature stop codon at position 2137. 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 breast and ovarian cancer and is the type of variant expected to cause the disorder. In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic. - |
| Pathogenic, no assertion criteria provided | clinical testing | Institute of Human Genetics, Medical University Innsbruck | Feb 11, 2015 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Nov 09, 2023 | The c.6405_6409del (p.Asn2135Lysfs*3) variant in the BRCA2 gene is located on the exon 11 and is predicted to cause shift of reading frame that introduces a premature translation termination codon (p.Asn2135Lysfs*3), resulting in an absent or disrupted protein product. The variant has been reported in multiple individuals with breast or ovarian cancer (PMID: 36171877, 31706072, 33606809, 30287823). Loss-of-function variants of BRCA2 are known to be pathogenic (PMID: 8988179, 11897832, 29446198). The variant is reported in ClinVar as pathogenic (ID: 38043) and reviewed by the expert panel. The variant is rare in the general population according to gnomAD (1/240630). Therefore, the c.6405_6409del (p.Asn2135Lysfs*3) variant of BRCA2 has been classified as pathogenic. - |
| 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:11
| Pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Sep 19, 2023 | The BRCA2 c.6405_6409del (p.Asn2135Lysfs*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 multiple affected individuals and families with breast and/or ovarian cancer (PMIDs: 36169650 (2022), 33646313 (2021), 33151324 (2021), 32341426 (2020), 32318955 (2020), 31825140 (2019), 31742824 (2020), 31090900 (2019), 30720863 (2019), 30287823 (2018), 30262796 (2018), 30078507 (2018), 29625052 (2018), 29161300 (2017), 28993434 (2018), 28831036 (2017), 28724667 (2017), 28324225 (2017), 27741520 (2016), 27425403 (2016), 21324516 (2011), 18489799 (2008), 17063270 (2007), 11179017 (2001), and 8988179 (1997)). The variant has been reported in breast cancer cases as well as in a control individual in a large scale breast cancer association study (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/BRCA2)). It has also been seen in biliary tract cancer (PMID: 36243179 (2022)), prostate cancer (PMIDs: 21952622 (2011) and 32853339 (2021)), and pancreatic cancer (PMID: 34399810 (2021)). The frequency of this variant in the general population, 0.0000042 (1/240630 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 | Revvity Omics, Revvity | Nov 29, 2022 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center | Mar 02, 2021 | PVS1, PS4 - |
| Pathogenic, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Nov 16, 2022 | PP5, PM2, PVS1 - |
| Pathogenic, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Clinical Genetics Laboratory, Skane University Hospital Lund | May 27, 2022 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Clinical Genetics and Genomics, Karolinska University Hospital | Jan 15, 2019 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Sep 01, 2023 | BRCA2: PVS1, PM2, PS4:Moderate - |
| 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 | GeneDx | Nov 28, 2022 | Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Not observed at a significant frequency in large population cohorts (gnomAD); Also known as 6633_6637delCTTAA and 6633del5; This variant is associated with the following publications: (PMID: 21324516, 21952622, 11179017, 12845657, 10326698, 27425403, 30287823, 34657373, 32980694, 9971877, 8988179, 25863477, 26026974, 25802882, 26687385, 25330149, 26843898, 26439132, 17063270, 18489799, 19967274, 20104584, 24156927, 16684319, 10464601, 12442265, 28127413, 28152038, 28985766, 29161300, 28831036, 28324225, 28724667, 28993434, 29909963, 30720863, 30078507, 30262796, 30720243, 30702160, 31090900, 27741520, 29625052, 26689913, 32318955, 31447099, 32581362, 33646313, 33151324, 34399810, 31825140, 32719484, 30875412, 30787465, 31742824, 33087929, 32359129, 32853339, 32341426, 32438681, 30040829, 35264596, 33804961, 32772980, 32986223) - |
| 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:4
| Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jan 09, 2021 | Variant summary: BRCA2 c.6405_6409delCTTAA (p.Asn2135LysfsX3) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 4.2e-06 in 240630 control chromosomes. c.6405_6409delCTTAA has been widely reported in the literature in multiple individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (example, Rebbeck_2018). These data indicate that the variant is very likely to be associated with disease. Multiple clinical diagnostic laboratories and one expert panel (ENIGMA) have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Apr 24, 2019 | The p.Asn2135LysfsX3 variant in BRCA2 has been reported in at least 12 individuals with BRCA2-associated cancers (Gayther 1997, Wagner 1999, Risch 2001, Gomes 2007, Machackova 2008, Kote-Jarai 2011, Zhang 2011, de Juan 2015, Hirotsu 2015, Breast Cancer Information Core database:www.research.nhgri.nih.gov/bic/). This variant has also been identified in 1/240630 of pan-ethnic 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 variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 2135 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 autosomal dominant HBOC. In addition, this variant was classified as Pathogenic on April 22, 2016 by the ClinGen-approved ENIGMA expert panel (ClinVar SCV000282424.1). In summary, this variant meets criteria to be classified as pathogenic for HBOC in an autosomal dominant manner based upon the predicted impact to the protein, presence in multiple affected individuals and very low frequency in the general population. ACMG/AMP Criteria applied: PVS1, PS4_Moderate, PM2. - |
| 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 | Labcorp Genetics (formerly Invitae), Labcorp | Jan 24, 2024 | This sequence change creates a premature translational stop signal (p.Asn2135Lysfs*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 (rs80359584, gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with breast, ovarian, and prostate cancer (PMID: 8988179, 11179017, 17063270, 21324516, 21952622, 25802882, 26026974). This variant is also known as c.6402_6406delTAACT, 6630del5, and 6633del5. ClinVar contains an entry for this variant (Variation ID: 38043). For these reasons, this variant has been classified as Pathogenic. - |
Hereditary cancer-predisposing syndrome Pathogenic:4
| Likely pathogenic, criteria provided, single submitter | research | Academic Department of Medical Genetics, University of Cambridge | Jan 26, 2018 | Application of AMCG guidelines 2015. Used other ClinVar submission evidence where relevant. Loss of heterozygosity in tumours or immunohistochemistry abnormalities considered functional evidence of pathogenicity. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Mar 08, 2023 | This variant deletes 5 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.6402_6406del, 6630del5, and 6633del5 in the literature. This variant has been reported in individuals affected with breast and/or ovarian cancer (PMID: 8988179, 11179017, 17063270, 18489799, 21324516, 25802882, 27425403, 29161300, 30287823). This variant has been identified in 1/240630 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 | Nov 22, 2021 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Apr 01, 2022 | The c.6405_6409delCTTAA pathogenic mutation, located in coding exon 10 of the BRCA2 gene, results from a deletion of 5 nucleotides at nucleotide positions 6405 to 6409, causing a translational frameshift with a predicted alternate stop codon (p.N2135Kfs*3). This mutation has been identified in multiple patients and families with hereditary breast and ovarian cancer syndrome (Gayther SA et al. Nat. Genet. 1997 Jan;15:103-5; Zhang S et al. Gynecol. Oncol. 2011 May;121:353-7; Kote-Jarai Z et al. Br. J. Cancer. 2011 Oct;105:1230-4; de Juan I et al. Fam. Cancer. 2015 Dec;14:505-13; Alemar B et al. Cancer Genet. 2016 Sep;209:417-422; Meisel C et al. Arch. Gynecol. Obstet. 2017 May;295(5):1227-1238; Li A et al. Gynecol. Oncol. 2018 10;151(1):145-152). Of note, this alteration is also designated as 6405delCTTAA, 6630del5, and 6633del5 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:2
| 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 | May 17, 2019 | - - |
BRCA2-related disorder Pathogenic:2
| Pathogenic, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Aug 16, 2024 | The BRCA2 c.6405_6409del5 variant is predicted to result in a frameshift and premature protein termination (p.Asn2135Lysfs*3). In the literature, this variant may be referred to as N2135fs, 6630del5, 6633_6637delCTTAA, 6633del5, or rs80359584. This variant has been repeatedly reported in individuals with various cancers such as breast, ovarian, prostate, and acute leukemia (reported as 6630del5 in Table 1, Gayther et al. 1997. PubMed ID: 8988179; reported as 6633del5 in Table 1, Risch et al. 2001. PubMed ID: 11179017; Table 2, Lhotova et al. 2020. PubMed ID: 32295079; reported as rs80359584 in Table S3, Darst et al. 2021. PubMed ID: 32853339). This variant has been reported in 1 of over 240,000 individuals in gnomAD, indicating that it is rare. In ClinVar, this variant is interpreted as pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/38043/). 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.6405_6409del;p.(Asn2135Lysfs*3) 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. This sequence change has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 38043; PMID: 21324516) - PS4. This variant is not present in population databases (rs80359584- gnomAD; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2. In summary, the currently available evidence indicates that the variant is pathogenic. - |
Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Department of Molecular Diagnostics, Institute of Oncology Ljubljana | Apr 02, 2020 | - - |
Breast neoplasm Pathogenic:1
| Pathogenic, criteria provided, single submitter | research | Laboratory of Molecular Diagnosis of Cancer, West China Hospital, Sichuan University | Nov 01, 2015 | - - |
Malignant tumor of pancreas Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | 3DMed Clinical Laboratory Inc | Nov 20, 2017 | - - |
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 03, 2024 | - - |
Breast carcinoma Pathogenic:1
| Pathogenic, no assertion criteria provided | clinical testing | Medical Genetics Laboratory, Umraniye Training and Research Hospital, University of Health Sciences | Sep 11, 2021 | - - |
not specified Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Jan 14, 2019 | The BRCA2 c.6405_6409delCTTAA variant (rs80359584) is reported in the medical literature in individuals with breast cancer or hereditary breast and ovarian cancer (Alemar 2016, Momozawa 2018, Wen 2018, Whitworth 2018). The variant is described as pathogenic by several sources in the ClinVar database (Variation ID: 38043) and is described in the general population with an allele frequency of 0.0004% (1/240630 alleles) in the Genome Aggregation Database. This variant causes a frameshift by deleting 5 nucleotides, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Considering available information, this variant is classified as pathogenic. References: Alemar B et al. Prevalence of Hispanic BRCA1 and BRCA2 mutations among hereditary breast and ovarian cancer patients from Brazil reveals differences among Latin American populations. Cancer Genet. 2016 Sep;209(9):417-422. Momozawa Y et al. Germline pathogenic variants of 11 breast cancer genes in 7,051 Japanese patients and 11,241 controls. Nat Commun. 2018 Oct 4;9(1):4083. doi: 10.1038/s41467-018-06581-8. Wen WX et al. Inherited mutations in BRCA1 and BRCA2 in an unselected multiethnic cohort of Asian patients with breast cancer and healthy controls from Malaysia. J Med Genet. 2018 Feb;55(2):97-103. Whitworth J et al. Comprehensive Cancer-Predisposition Gene Testing in an Adult Multiple Primary Tumor Series Shows a Broad Range of Deleterious Variants and Atypical Tumor Phenotypes. Am J Hum Genet. 2018 Jul 5;103(1):3-18. - |
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Find out detailed SpliceAI scores and Pangolin per-transcript scores at