ClinVar Miner

Submissions for variant NM_000059.4(BRCA2):c.6405_6409del (p.Asn2135fs)

dbSNP: rs80359584
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Total submissions: 48
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) RCV000031625 SCV000282424 pathogenic Breast-ovarian cancer, familial, susceptibility to, 2 2016-04-22 reviewed by expert panel curation Variant allele predicted to encode a truncated non-functional protein.
Labcorp Genetics (formerly Invitae), Labcorp RCV000044934 SCV000072947 pathogenic Hereditary breast ovarian cancer syndrome 2025-01-14 criteria provided, single submitter clinical testing 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.
GeneDx RCV000160301 SCV000210779 pathogenic not provided 2022-11-28 criteria provided, single submitter clinical testing 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)
Ambry Genetics RCV000162930 SCV000213417 pathogenic Hereditary cancer-predisposing syndrome 2025-01-24 criteria provided, single submitter clinical testing The c.6405_6409delCTTAA (p.N2135Kfs*3) alteration, located in exon 11 (coding exon 10) of the BRCA2 gene, consists of a deletion of 5 nucleotides from position 6405 to 6409, causing a translational frameshift with a predicted alternate stop codon after 3 amino acids. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. Based on data from gnomAD, this allele has an overall frequency of <0.001% (1/240630) total alleles studied. This alteration has been identified in multiple patients and families with hereditary breast and ovarian cancer syndrome (Gayther, 1997; Zhang, 2011; Kote-Jarai, 2011; de Juan, 2015; Alemar, 2016; Meisel, 2017; Li, 2018). Of note, this alteration is also designated as 6405delCTTAA, 6630del5, and 6633del5 in published literature. Based on the available evidence, this alteration is classified as pathogenic.
Laboratory of Molecular Diagnosis of Cancer, West China Hospital, Sichuan University RCV000240801 SCV000265903 pathogenic Breast neoplasm 2015-11-01 criteria provided, single submitter research
Color Diagnostics, LLC DBA Color Health RCV000162930 SCV000292150 pathogenic Hereditary cancer-predisposing syndrome 2024-07-23 criteria provided, single submitter clinical testing 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.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000160301 SCV000296661 pathogenic not provided 2023-09-19 criteria provided, single submitter clinical testing 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.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000031625 SCV000327416 pathogenic Breast-ovarian cancer, familial, susceptibility to, 2 2015-10-02 criteria provided, single submitter clinical testing
Baylor Genetics RCV000456954 SCV000541014 pathogenic Familial cancer of breast 2024-03-03 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000044934 SCV000605796 pathogenic Hereditary breast ovarian cancer syndrome 2019-04-24 criteria provided, single submitter clinical testing 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000044934 SCV000694970 pathogenic Hereditary breast ovarian cancer syndrome 2021-01-09 criteria provided, single submitter clinical testing 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.
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center RCV000031625 SCV000744491 pathogenic Breast-ovarian cancer, familial, susceptibility to, 2 2017-05-31 criteria provided, single submitter clinical testing
3DMed Clinical Laboratory Inc RCV000677858 SCV000804019 pathogenic Malignant tumor of pancreas 2017-11-20 criteria provided, single submitter clinical testing
Academic Department of Medical Genetics, University of Cambridge RCV000162930 SCV000992214 likely pathogenic Hereditary cancer-predisposing syndrome 2018-01-26 criteria provided, single submitter research 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.
Mendelics RCV000031625 SCV001139150 pathogenic Breast-ovarian cancer, familial, susceptibility to, 2 2019-05-28 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000160301 SCV001160240 pathogenic not provided 2024-09-12 criteria provided, single submitter clinical testing The BRCA2 c.6405_6409del; p.Asn2135LysfsTer3 variant (rs80359584) is reported in the medical literature in individuals with breast cancer or hereditary breast and ovarian cancer syndrome (Alemar 2016, Deng 2019, Momozawa 2018, Wen 2018, Whitworth 2018). This variant is only observed on one allele (1/240,630 chromosomes) in the Genome Aggregation Database (v2.1.1), indicating it is not a common polymorphism. This variant causes a frameshift by deleting five nucleotides, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Considering available information, this variant is considered to be 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. PMID: 27425403. Deng M et al. Prevalence and clinical outcomes of germline mutations in BRCA1/2 and PALB2 genes in 2769 unselected breast cancer patients in China. Int J Cancer. 2019 Sep 15;145(6):1517-1528. PMID: 30720863. 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. PMID: 30287823. 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. PMID: 28993434. 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. PMID: 29909963.
Institute of Genomics, University of Tartu RCV000031625 SCV001430701 pathogenic Breast-ovarian cancer, familial, susceptibility to, 2 criteria provided, single submitter research
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen RCV000160301 SCV001446832 pathogenic not provided 2020-10-23 criteria provided, single submitter clinical testing
Clinical Genetics and Genomics, Karolinska University Hospital RCV000160301 SCV001450398 pathogenic not provided 2019-01-15 criteria provided, single submitter clinical testing
Department of Molecular Diagnostics, Institute of Oncology Ljubljana RCV001310128 SCV001499676 pathogenic Breast-ovarian cancer, familial, susceptibility to, 1 2020-04-02 criteria provided, single submitter clinical testing
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden RCV000160301 SCV002010339 pathogenic not provided 2021-11-03 criteria provided, single submitter clinical testing
Revvity Omics, Revvity RCV000160301 SCV002020299 pathogenic not provided 2022-11-29 criteria provided, single submitter clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario RCV001271044 SCV002043339 pathogenic Breast and/or ovarian cancer 2019-05-17 criteria provided, single submitter clinical testing
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center RCV000160301 SCV002051607 pathogenic not provided 2021-03-02 criteria provided, single submitter clinical testing PVS1, PS4
DASA RCV001849286 SCV002107098 pathogenic BRCA2-related disorder 2022-03-05 criteria provided, single submitter clinical testing 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.
Sema4, Sema4 RCV000162930 SCV002536231 pathogenic Hereditary cancer-predisposing syndrome 2021-11-22 criteria provided, single submitter curation
CeGaT Center for Human Genetics Tuebingen RCV000160301 SCV004042561 pathogenic not provided 2023-09-01 criteria provided, single submitter clinical testing BRCA2: PVS1, PM2, PS4:Moderate
Mayo Clinic Laboratories, Mayo Clinic RCV000160301 SCV004226599 pathogenic not provided 2024-01-30 criteria provided, single submitter clinical testing PM5_strong, PVS1
All of Us Research Program, National Institutes of Health RCV004803060 SCV004844257 pathogenic BRCA2-related cancer predisposition 2024-09-16 criteria provided, single submitter clinical testing 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.
Clinical Genetics Laboratory, Skane University Hospital Lund RCV000160301 SCV005198261 pathogenic not provided 2022-05-27 criteria provided, single submitter clinical testing
Fulgent Genetics, Fulgent Genetics RCV005007914 SCV005633951 pathogenic Familial cancer of breast; Breast-ovarian cancer, familial, susceptibility to, 2; Fanconi anemia complementation group D1; Medulloblastoma; Wilms tumor 1; Pancreatic cancer, susceptibility to, 2; Glioma susceptibility 3; Familial prostate cancer 2024-03-25 criteria provided, single submitter clinical testing
Genomics and Molecular Medicine Service, East Genomic Laboratory Hub, NHS Genomic Medicine Service RCV005237443 SCV005882946 pathogenic Inherited breast cancer and ovarian cancer 2024-10-16 criteria provided, single submitter clinical testing PVS1,PM5_Strong
Institute of Human Genetics, FAU Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg RCV000160301 SCV006082268 pathogenic not provided 2025-05-30 criteria provided, single submitter clinical testing This variant has been identified by standard clinical testing. Female patient with triple-negative breast cancer Selected ACMG criteria: Not enough evidence
Sharing Clinical Reports Project (SCRP) RCV000031625 SCV000054232 pathogenic Breast-ovarian cancer, familial, susceptibility to, 2 2012-07-02 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000031625 SCV000146844 pathogenic Breast-ovarian cancer, familial, susceptibility to, 2 2002-05-29 no assertion criteria provided clinical testing
Institute of Human Genetics, Medical University Innsbruck RCV000031625 SCV000212026 pathogenic Breast-ovarian cancer, familial, susceptibility to, 2 2015-02-11 no assertion criteria provided clinical testing
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto RCV000044934 SCV000587843 pathogenic Hereditary breast ovarian cancer syndrome 2014-01-31 no assertion criteria provided research
Department of Pathology and Laboratory Medicine, Sinai Health System RCV000031625 SCV000592048 pathogenic Breast-ovarian cancer, familial, susceptibility to, 2 no assertion criteria provided clinical testing 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.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen RCV000031625 SCV000733282 pathogenic Breast-ovarian cancer, familial, susceptibility to, 2 no assertion criteria provided clinical testing
Counsyl RCV000031625 SCV000785311 pathogenic Breast-ovarian cancer, familial, susceptibility to, 2 2017-07-05 no assertion criteria provided clinical testing This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com.
CZECANCA consortium RCV001271044 SCV001451863 pathogenic Breast and/or ovarian cancer 2019-06-11 no assertion criteria provided clinical testing
Medical Genetics Laboratory, Umraniye Training and Research Hospital, University of Health Sciences RCV001642418 SCV001852765 pathogenic Breast carcinoma 2021-09-11 no assertion criteria provided clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ RCV000160301 SCV001958038 pathogenic not provided no assertion criteria provided clinical testing
Laboratory for Genotyping Development, RIKEN RCV003162277 SCV002758337 pathogenic Gastric cancer 2021-07-01 no assertion criteria provided research
Zotz-Klimas Genetics Lab, MVZ Zotz Klimas RCV000031625 SCV004171660 pathogenic Breast-ovarian cancer, familial, susceptibility to, 2 2023-11-24 no assertion criteria provided clinical testing
BRCAlab, Lund University RCV000031625 SCV004243716 pathogenic Breast-ovarian cancer, familial, susceptibility to, 2 2020-03-02 no assertion criteria provided clinical testing
Molecular Oncology, Hospital Universitario Central de Asturias (HUCA) RCV000031625 SCV005061335 pathogenic Breast-ovarian cancer, familial, susceptibility to, 2 2021-05-24 no assertion criteria provided case-control
PreventionGenetics, part of Exact Sciences RCV001849286 SCV005358611 pathogenic BRCA2-related disorder 2024-08-16 no assertion criteria provided clinical testing 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.

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