rs80359550
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Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM3_StrongPM5_StrongPVS1
This summary comes from the ClinGen Evidence Repository: The c.5946del variant in BRCA2 is a deletion of a single nucleotide, predicted to encode a frameshift with consequent premature termination of the protein at codon 22 of the frameshift, or amino acid 2003 (p.Ser1982ArgfsTer22). This deletion variant was not observed in gnomAD v2.1 (exomes only, non-cancer subset) or gnomAD v3.1 (non-cancer subset), but PM2_Supporting was not applied since recall is suboptimal for this type of variant (PM2_Supporting not met). Frameshift variant predicted to cause a premature stop codon in biologically-relevant-exon 11 leading to nonsense mediated decay (PVS1 met). The ENIGMA BRCA1/2 VCEP considered multiple lines of functional and clinical evidence to define exon-specific weights for PTC in BRCA2, and results indicate that strong evidence towards pathogenicity may be applied for a PTC variant in BRCA2 exon 11 (PM5_Strong (PTC)). This variant has been detected in 6 individuals with phenotype consistent with BRCA2-Fanconi Anemia (FA). At least two clinical features of FA (physical features, pathology findings and cancer diagnosis ≤5yr) and confirmed chromosome breakage, are seen in these individuals. 6 were compound heterozygous for the variant and a pathogenic or likely pathogenic variant, and confirmed to be in trans. Total points equated to 8 (PM3_Strong met; PMIDs: 14559878, 15516848, 16825431, 19530235). In summary, this variant meets the criteria to be classified as a Pathogenic variant for BRCA2-related cancer predisposition based on the ACMG/AMP criteria applied as specified by the ENIGMA BRCA1/2 VCEP (PVS1, PM5_Strong (PTC), PM3_Strong). LINK:https://erepo.genome.network/evrepo/ui/classification/CA023403/MONDO:0012933/097
Frequency
Genomes: 𝑓 0.00017 ( 0 hom., cov: 33)
Exomes 𝑓: 0.00014 ( 0 hom. )
Consequence
BRCA2
NM_000059.4 frameshift
NM_000059.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 2.83
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
For more information check the summary or visit ClinGen Evidence Repository.
PM3
For more information check the summary or visit ClinGen Evidence Repository.
PM5
For more information check the summary or visit ClinGen Evidence Repository.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| BRCA2 | NM_000059.4 | c.5946del | p.Ser1982ArgfsTer22 | 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.5946del | p.Ser1982ArgfsTer22 | frameshift_variant | 11/27 | 5 | NM_000059.4 | ENSP00000369497 | A2 |
Frequencies
GnomAD3 genomes 0.000171 AC: 26AN: 152158Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.000291 AC: 73AN: 250700Hom.: 0 AF XY: 0.000236 AC XY: 32AN XY: 135772
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GnomAD4 genome 0.000171 AC: 26AN: 152158Hom.: 0 Cov.: 33 AF XY: 0.000161 AC XY: 12AN XY: 74360
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:73Other:3
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
Breast-ovarian cancer, familial, susceptibility to, 2 Pathogenic:28
| Pathogenic, criteria provided, single submitter | clinical testing | New York Genome Center | Mar 31, 2022 | The c.5946del, p.Ser1982ArgfsTer22 missense variant identified in BRCA2, also known as c.6174delT, results in a frameshift and premature termination of the protein. The p.Ser1982ArgfsTer22 variant is a founder variant in the BRCA2 gene that is prevalent in the Ashkenazi Jewish and Icelandic populations, and has been previously reported as a heterozygous change in multiple individuals with a personal or family history of breast and/or ovarian cancer, among other types of cancer (PMID: 20301425, 29084914, 29433453, 29321669, 28767289). Based on the available evidence, the c.5946delT, p.Ser1982ArgfsTer22 variant is classified as pathogenic. - |
| Pathogenic, no assertion criteria provided | clinical testing | Breast Cancer Information Core (BIC) (BRCA2) | May 29, 2002 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine | May 24, 2017 | The c.5946del (p.Ser1982Argfs*22) variant has been detected in a multiple patients with breast and ovarian cancer [reported as c.6174del in PMID 8673091, 23633455, 22006311, 21324516, 22430266]. The variant was also detected in patients with prostate cancer [PMID 19188187, 20736950] and pancreatic ductal adenocarcinoma [PMID 23658460]. This variant is associated with a cancer risk of 50-43% and 18-20% risk for breast and ovarian cancer respectively by age 70 [PMID 9145676,15994883]. In vitro assays showed that this variant leads to a loss of function of the protein [PMID 15695382]. This variant has been reported in 32 non-Finnish Europeans from the ExAC database (http://exac.broadinstitute.org/variant/13-32914437-GT-G). This c.5946del (p.Ser1982Argfs*22) variant occurs at high frequency in the Ashkenazi Jewish population and is considered a founder mutation in this population. This variant is thus classified as pathogenic.[leduc, 2017-03-07] - |
| Pathogenic, criteria provided, single submitter | research | Department of Pediatrics, Memorial Sloan Kettering Cancer Center | Dec 15, 2020 | - - |
| Pathogenic, no assertion criteria provided | literature only | OMIM | Dec 21, 1995 | - - |
| 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 | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The BRCA2 p.Ser1982Argfs*22 variant was identified in 33 of 11966 proband chromosomes (frequency: 0.003) from individuals or families with breast, ovarian and pancreatic cancer (Agalliu 2009, Borg 2010, Couch 2014, Edwards 2010, Zhang 2011). The variant was also identified in dbSNP (ID: rs80359550) as “With Pathogenic allele”, ClinVar (classified as pathogenic by 34 submitters including Invitae, GeneDx, Counsyl, ARUP and Ambry Genetics), COGR (3 entries classified as pathogenic), COSMIC (1x confirmed somatic in adenocarcinoma of the pancreas), LOVD 3.0 (110 entries classified as affects function), UMD-LSDB (75 entries classified as causal), BIC Database (1090 entries classified as pathogenic), ARUP Laboratories (classified as definitely pathogenic), and the Zhejiang Colon Cancer Database (classified as pathogenic). The variant was not identified in the MutDB database. The variant was also identified by our laboratory in multiple individuals with breast, ovarian or pancreatic cancer. The variant was identified in control databases in 72 of 276978 chromosomes at a frequency of 0.0003 (Genome Aggregation Database Feb 27, 2017). It was observed in the following populations: Ashkenazi Jewish in 59 of 10150 chromosomes (freq: 0.006), Other in 3 of 6460 chromosomes (freq: 0.0005), European (Non-Finnish) in 10 of 126512 chromosomes (freq: 0.00008); it was not observed in the African, East Asian, European (Finnish), Latino, or South Asian populations. The c.5946delT variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 1982 and leads to a premature stop codon 22 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. The truncating BRCA2 6174delT Ashkenazi Jewish founder mutation is associated with a breast cancer risk of 70% by age 70 and identified in the vast majority of Ashkenazi Jewish families with a history of breast and ovarian cancer (Pohlreich 2005, Wu 2005). In addition, a functional study using bacterial artificial chromosomes concluded that this mutation could not rescue lethality in BRCA2-deficient mouse embryonic stem cells, supporting its classification as deleterious (Kuznetsov 2008). In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic. Assessment Date: 2018/03/07. - |
| Pathogenic, criteria provided, single submitter | literature only | Counsyl | Apr 07, 2014 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Sharing Clinical Reports Project (SCRP) | Jan 15, 2013 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | Jan 04, 2021 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Michigan Medical Genetics Laboratories, University of Michigan | Nov 03, 2014 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Jul 02, 2023 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Division Of Personalized Genomic Medicine, Columbia University Irving Medical Center | Mar 09, 2021 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Equipe Genetique des Anomalies du Developpement, Université de Bourgogne | Nov 07, 2017 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Johns Hopkins Genomics, Johns Hopkins University | May 03, 2022 | This variant (rs28897738) has been reported in the literature in association with a variety of BRCA2-related cancer conditions that are inherited in a dominant or recessive manner. It is known as a founder mutation in the Ashkenazi Jewish population and has also been observed in individuals of non-Ashkenazi Jewish descent. It is rare (<0.1%) in a large population dataset (gnomAD: 78/282088 total alleles; 0.0277%; no homozygotes) and has been reported in ClinVar(Variation ID 9325). This frameshift variant results in a premature stop codon in exon 11, likely leading to nonsense-mediated decay and lack of protein production and has supporting functional evidence. We consider this variant to be pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet | May 27, 2024 | PM3_Strong; PVS1; PM5_PTC_Strong - |
| Pathogenic, criteria provided, single submitter | clinical testing | MGZ Medical Genetics Center | Aug 02, 2022 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Feb 05, 2024 | The c.5946del (p.Ser1982Argfs*22) variant has been detected in a multiple patients with breast and ovarian cancer [reported as c.6174del in PMID 8673091, 23633455, 22006311, 21324516, 22430266]. The variant was also detected in patients with prostate cancer [PMID 19188187, 20736950] and pancreatic ductal adenocarcinoma [PMID 23658460]. This variant is associated with a cancer risk of 50-43% and 18-20% risk for breast and ovarian cancer respectively by age 70 [PMID 9145676,15994883]. In vitro assays showed that this variant leads to a loss of function of the protein [PMID 15695382]. This variant has been reported in 32 non-Finnish Europeans from the ExAC database (http://exac.broadinstitute.org/variant/13-32914437-GT-G). This variant occurs at high frequency in the Ashkenazi Jewish population and is considered a founder mutation in this population. This variant is classified as pathogenic and considered medically actionable. [leduc, 2017-03-07] The c.5946del (p.Ser1982Argfs*22) variant has been detected in a multiple patients with breast and ovarian cancer [reported as c.6174del in PMID 8673091, 23633455, 22006311, 21324516, 22430266]. The variant was also detected in patients with prostate cancer [PMID 19188187, 20736950] and pancreatic ductal adenocarcinoma [PMID 23658460]. This variant is associated with a cancer risk of 50-43% and 18-20% risk for breast and ovarian cancer respectively by age 70 [PMID 9145676,15994883]. In vitro assays showed that this variant leads to a loss of function of the protein [PMID 15695382]. This variant has been reported in 32 non-Finnish Europeans from the ExAC database (http://exac.broadinstitute.org/variant/13-32914437-GT-G). This c.5946del (p.Ser1982Argfs*22) variant occurs at high frequency in the Ashkenazi Jewish population and is considered a founder mutation in this population. This variant is thus classified as pathogenic. - |
| Pathogenic, no assertion criteria provided | clinical testing | BRCAlab, Lund University | Aug 26, 2022 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Genetics and Molecular Pathology, SA Pathology | Apr 17, 2020 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | May 16, 2016 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Feb 12, 2016 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Department of Medical Genetics, Oslo University Hospital | Jul 01, 2015 | - - |
| 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 | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Department of Human Genetics, Hannover Medical School | Jul 04, 2024 | - - |
| Pathogenic, no assertion criteria provided | research | Centro de Genética y Biología Molecular, Universidad de San Martín de Porres | Jun 10, 2015 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Pathway Genomics | Jul 24, 2014 | - - |
not provided Pathogenic:19
| Pathogenic, criteria provided, single submitter | clinical testing | Clinical Genetics and Genomics, Karolinska University Hospital | Aug 07, 2014 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Feb 03, 2017 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jun 11, 2020 | Common founder variant in the Ashkenazi Jewish population (Oddoux 1996); 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; Published functional studies demonstrate a damaging effect: increased sensitivity to MMC, decreased HDR, and increased centrosome amplification compared to wild-type (Wu 2005); Observed in approximately 1% of the Ashkenazi Jewish population (Oddoux 1996); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Also known as 6174delT; This variant is associated with the following publications: (PMID: 20736950, 20887823, 28049106, 28291774, 30620386, 27836010, 23633455, 15695382, 19188187, 22703879, 22009639, 22430266, 23658460, 23341105, 22006311, 21324516, 8673091, 25980754, 26440929, 27425403, 14559878, 26681312, 29321669, 29339979, 29433453, 29368341, 29084914, 27989354, 29907814, 26556299, 10464624, 28767289, 8841192, 29161300, 29439820, 30274973, 30152102, 29506128, 30122538, 30716324, 30186769, 30720243, 29961768, 30702160, 29978187, 30322717, 29937315, 30113427, 30489631, 31263054, 31444830, 32438681, 31512090, 29625052, 26689913, 31447099, 31948886, 34308366, 10739756, 10733239, 34399810, 33077847, 31589614, 32853339, 32341426, 32719484, 32885271, 32338768, 30787465, 30613976, 33087929) - |
| Pathogenic, criteria provided, single submitter | clinical testing | Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden | Nov 03, 2021 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Nov 16, 2023 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Jul 31, 2024 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Human Genetics Bochum, Ruhr University Bochum | Oct 04, 2023 | ACMG criteria used to clasify this variant:PVS1, PS4 - |
| 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 | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Nov 27, 2023 | The BRCA2 c.5946delT; p.Ser1982ArgfsTer22 variant (rs80359550), also published as 6174delT, is reported as a pathogenic founder variant in the Ashkenazi Jewish population (Abeliovich 1997, Couch 1996, Finkelman 2012), and has been associated with hereditary breast and ovarian cancer syndrome. The variant is reported as pathogenic by several sources in the ClinVar database (Variation ID: 9325) and is found in the Ashkenazi Jewish population with an allele frequency of 0.6% (61/10,364 alleles) in the Genome Aggregation Database. This variant causes a frameshift by deleting a single nucleotide, 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 to be pathogenic. [**Use the AJ BRCA template under BRCA NGS, OR Make sure to add the AJ recommendations from that template "If this individual is of Ashkenazi Jewish ancestry…"**] References: Abeliovich D et al. The founder mutations 185delAG and 5382insC in BRCA1 and 6174delT in BRCA2 appear in 60% of ovarian cancer and 30% of early-onset breast cancer patients among Ashkenazi women. Am J Hum Genet. 1997 Mar;60(3):505-14. PMID: 9042909. Couch FJ et al. BRCA2 germline mutations in male breast cancer cases and breast cancer families. Nat Genet. 1996 May;13(1):123-5. PMID: 8673091. Finkelman BS et al. Breast and ovarian cancer risk and risk reduction in Jewish BRCA1/2 mutation carriers. J Clin Oncol. 2012 Apr 20;30(12):1321-8. PMID: 22430266. - |
| Pathogenic, no assertion criteria provided | clinical testing | Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Jun 28, 2023 | PP5, PS4_moderate, PVS1 - |
| Pathogenic, criteria provided, single submitter | clinical testing | Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen | Jun 17, 2021 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | GeneKor MSA | Jan 01, 2020 | This variant is a deletion of one nucleotide, resulting in a frameshift and the creation of a novel translational stop codon after 22 amino acid residues. The protein product thus produced is truncated and non-functional. Truncating variants in BRCA2 are known to be pathogenic. In the literature, this variant is also known as 6174delT and is a common cause of breast and ovarian cancer in the Ashkenazi Jewish population (PMID: 9042909, 22430266). Moreover, it has been reported in individuals of other ethnicities (PMID: 8758903, 10417300). This variant has been associated with a 43% to 55% risk of breast cancer by age 70, and a 20% to 37% risk of ovarian cancer by age 70 (PMID: 15994883). The mutation database ClinVar contains entries for this variant (Variation ID: 9325). - |
| Pathogenic, criteria provided, single submitter | research | Gharavi Laboratory, Columbia University | Sep 16, 2018 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Clinical Genetics Laboratory, Skane University Hospital Lund | May 27, 2022 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Aug 19, 2021 | This frameshift variant alters the translational reading frame of the BRCA2 mRNA and causes the premature termination of BRCA2 protein synthesis. The frequency of this variant in the general population, 0.00011 (14/128890 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported as a BRCA2 founder variant in the Ashkenazi Jewish population with a carrier frequency of approximately 1.52% (PMID: 17591843 (2007) and 8841191 (1996)). Based on the available information, this variant is classified as pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jun 01, 2024 | BRCA2: PVS1, PS4:Moderate, PM2:Supporting - |
Hereditary breast ovarian cancer syndrome Pathogenic:9Other:1
| Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | May 01, 2019 | Variant summary: BRCA2 c.5946delT (p.Ser1982ArgfsX22) 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. The variant allele was found at a frequency of 0.0002765 in 282088 control chromosomes (gnomAD), which does not exceed the estimated maximal expected allele frequency of a pathogenic BRCA2 variant (0.0007503) and was predominantly observed in the Ashkenazi Jewish subpopulation. This variant is a well-established Ashkenazi Jewish founder mutation. The variant, c.5946delT, has been reported in the literature in multiple individuals affected with Hereditary Breast and Ovarian Cancer (Abeliovich_1997, Friedman_1998). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function (Wu_2005). Multiple ClinVar submissions after 2014 cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
| 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.Ser1982Argfs*22) 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 (rs80359550, gnomAD 0.6%). This premature translational stop signal has been observed in individual(s) with breast (43% to 55% lifetime risk) and/or ovarian cancer (20% to 37% lifetime risk) (PMID: 8758903, 9042909, 10417300, 15994883, 22430266). It is commonly reported in individuals of Ashkenazi Jewish ancestry (PMID: 8758903, 9042909, 10417300, 22430266). This premature translational stop signal has been observed to co-occur in individuals with a different variant in BRCA2 that has been determined to be pathogenic (Invitae), but the significance of this finding is unclear. This variant is also known as 6174delT. ClinVar contains an entry for this variant (Variation ID: 9325). For these reasons, this variant has been classified as Pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | National Health Laboratory Service, Universitas Academic Hospital and University of the Free State | Nov 16, 2021 | - - |
| Pathogenic, no assertion criteria provided | research | Curoverse | Aug 01, 2015 | Frameshifts in BRCA2 are considered pathogenic, and this is a BRCA2 Ser1982Arg frameshift variant in exon 11 - |
| not provided, no classification provided | literature only | GeneReviews | - | Founder variant in Ashkenazi Jews; accounts for 95% of pathogenic variants in this population - |
| Pathogenic, criteria provided, single submitter | clinical testing | St. Jude Molecular Pathology, St. Jude Children's Research Hospital | Mar 22, 2022 | The BRCA2 c.5946del (p.Ser1982ArgfsTer22) change causes a frameshift and the creation of a premature stop codon. This change is predicted to cause protein truncation or absence of the protein due to nonsense mediated decay (PVS1). This variant has a maximum subpopulation frequency of 0.59% in gnomAD v2.1.1, where it is primarily found in the Ashkenazi Jewish population (https://gnomad.broadinstitute.org/variant/13-32914437-GT-G?dataset=gnomad_r2_1). This variant has been reported in multiple individuals with breast cancer and/or ovarian cancer (PMID: 8673092, 9042909, 9150153, 15994883, 22430266, 30152102). It is a well-established pathogenic founder variant in the Ashkenazi Jewish population (PMID: 9042909, 22430266). This alteration is also known as 6174delT in the literature. In summary, this variant meets criteria to be classified as pathogenic based on the ACMG/AMP criteria: PVS1, PS4. - |
| 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 | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jun 07, 2023 | The p.Ser1982ArgfsX22 variant in BRCA2 is a founder mutation in the Ashkenazi Jewish population (Finkelman 2012 PMID: 22430266) and has been identified in >500 individuals of various ethnicities with BRCA2-associated cancers (Breast Cancer Information Core (BIC) database: https://research.nhgri.nih.gov/projects/bic/). It has also been identified in 0.6% (20/3466) of Ashkenazi Jewish and 0.009% (6/68002) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org, v.3.1.2). This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 1982 and leads to a premature termination codon 22 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Heterozygous loss of function BRCA2 is an established disease mechanism for hereditary breast and ovarian cancer (HBOC) syndrome. Additionally, this variant was classified as pathogenic on April 22, 2016 by the ClinGen-approved ENIGMA expert panel (ClinVar variation ID 9325). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant HBOC. ACMG/AMP Criteria applied: PVS1, PS4_Strong. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Mendelics | Jul 02, 2018 | - - |
| Pathogenic, no assertion criteria provided | research | Biesecker Lab/Clinical Genomics Section, National Institutes of Health | Jul 13, 2012 | - - |
Hereditary cancer-predisposing syndrome Pathogenic:6
| Pathogenic, criteria provided, single submitter | clinical testing | Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C. | Jul 12, 2017 | - - |
| Pathogenic, criteria provided, single submitter | curation | Sema4, Sema4 | Oct 23, 2021 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | True Health Diagnostics | Sep 27, 2017 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Mar 06, 2023 | This variant deletes 1 nucleotide in exon 11 of the BRCA2 gene, causing a frameshift and a premature translational stop signal. This variant is also known as 6174delT in the literature. This variant is expected to result in an absent or non-functional protein product. Functional studies have reported that this variant impacts BRCA2 function in homology-directed repair and other ancillary assays (PMID: 15695382, 18607349). This variant is a well-known founder mutation in the Ashkenazi Jewish population and occurs at 0.6-1.52% minor allele frequency (PMID: 8673092, 30152102). This variant has been reported in dozens of individuals affected with breast and/or ovarian cancer in Ashkenazi Jewish and in non-Ashkenazi Jewish populations (PMID: 8524414, 8673091, 8673092, 8758903, 8898735, 8841191, 9145676, 12473589, 14576434, 20104584, 21324516, 22006311, 22430266, 28944232, 29084914, 29433453). This variant has been reported with cosegregation likelihood ratio for pathogenicity of over 1,000 (PMID: 15695382) and in a breast cancer case-control meta-analysis in 26/60440 cases and 8/53453 unaffected individuals with OR 2.874 (95%CI 1.301 to 6.349) (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA2_000149). The risk of female breast cancer among carriers of this mutation is 43-55% by age 70, and the risk of ovarian cancer is 18-37% by age 70 (PMID: 9145676, 15994883, 22430266). This variant has been identified in 78/282088 chromosomes in the general population (61/10364 Ashkenazi Jewish chromosomes) 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 | Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego | Aug 14, 2018 | This variant is also known as c.6174delT using alternate nomenclature. This variant is known as a founder mutation in the Ashkenazi Jewish population (PMID: 20301425) and has been previously reported as a heterozygous change in multiple individuals with a personal or family history of breast and/or ovarian cancer, among other types of cancer (PMID: 20301425, 29084914, 29433453, 2644092, 29321669, 28767289). Based on the available evidence, the c.5946delT (p.Ser1982ArgfsTer22) variant is classified as pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 13, 2022 | The c.5946delT (p.S1982Rfs*22) alteration, located in exon 11 (coding exon 10) of the BRCA2 gene, consists of a deletion of one nucleotide at position 5946, causing a translational frameshift with a predicted alternate stop codon after 22 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 0.028% (78/282088) total alleles studied. The highest observed frequency was 0.589% (61/10364) of Ashkenazi Jewish alleles. This variant is one of the well-described Ashkenazi Jewish founder mutations and has been reported in numerous families affected with breast, ovarian, prostate, pancreatic, and other HBOC-related cancers (Agalliu, 2009; Walsh, 2011; Johnston, 2012; Bayraktar, 2012; George, 2013; Lucas, 2013; Salo-Mullen, 2015; Susswein, 2016). Another study indicated that carriers of the c.5946delT variant may have a lower relative risk for breast cancer when compared to carriers of other non-Ashkenazi Jewish BRCA2 likely pathogenic/pathogenic variants (Finkelman, 2012). This variant is also designated as 6174delT in published literature. Based on the available evidence, this alteration is classified as pathogenic. - |
Familial cancer of breast Pathogenic:3
| Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 29, 2024 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | May 06, 2024 | Criteria applied: PVS1,PM5_STR - |
| Pathogenic, no assertion criteria provided | clinical testing | Bioscientia Institut fuer Medizinische Diagnostik GmbH, Sonic Healthcare | - | - - |
BRCA2-related disorder Pathogenic:2
| Pathogenic, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 28, 2017 | The BRCA2 c.5946delT (p.Ser1982ArgfsTer22) variant, more commonly known as c.6174delT, results in a frameshift and premature termination of the protein. The p.Ser1982ArgfsTer22 variant is a well-described founder variant in the BRCA2 gene that is prevalent in the Ashkenazi Jewish and Icelandic populations, with a carrier frequency of ~1.5% (Roa et al. 1996; Neuhausen et al. 1996). The variant has been shown to occur in approximately eight percent of women diagnosed with breast cancer before the age of 42 years (Neuhausen et al. 1996; Oddoux et al. 1996; Petrucelli et al. 2010; Finkelman et al. 2012). By the age of 70, 43% of individuals who carry this variant are predicted to develop breast cancer and 20% are predicted to develop ovarian cancer (Struewing et al. 1997; King et al. 2003). Across a selection of the literature, the p.Ser1982ArgfsTer22 variant has been identified in 55 of 1,272 (4%) individuals with breast cancer, 44 of 382 (11.5%) individuals with ovarian cancer, and at least 118 of 9,658 (1.2%) Ashkenazi Jewish individuals from the general population (Couch et al. 1996; Roa et al. 1996; Neuhausen et al. 1996; Oddoux et al. 1996; Struewing et al. 1997; Satagopan et al. 2002; King et al. 2003). Additionally, the p.Ser1982ArgfsTer22 variant has been identified in a compound heterozygous state in four individuals, including two cousins, with Fanconi anemia and brain tumors from three different Ashkenazi Jewish families (Offit et al. 2003; Alter et al. 2007). The p.Ser1982ArgfsTer22 variant was absent from at least 1,726 non-Ashkenazi Jewish controls and is reported at a frequency of 0.00048 in the European (non-Finnish) population of the Exome Aggregation Consortium. Functional studies demonstrated decreased cell viability and survival in carriers of the p.Ser1982ArgfsTer22 variant (Wu et al. 2005). The variant protein was shown to be localized in the cytoplasm and not in the nucleus. The p.Ser1982ArgfsTer22 variant is predicted to result in truncation of approximately 41% of the BRCA2 protein, which would remove two signals required for nuclear localization and represents a likely mode of pathogenicity for the variant (Spain et al. 1999). In a study in mouse embryonic stem cells, the p.Ser1982ArgfsTer22 variant failed to rescue the loss of endogenous BRCA2 (Kuznetsov et al. 2008). Based on the collective evidence, the p.Ser1982ArgfsTer22 variant is classified as pathogenic for BRCA2-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. - |
| Pathogenic, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Jul 17, 2024 | The BRCA2 c.5946delT variant is predicted to result in a frameshift and premature protein termination (p.Ser1982Argfs*22). This variant, also described as 6174delT in the literature, has been associated with autosomal dominant hereditary breast and ovarian cancer syndrome (HBOC) (OMIM #612555; Couch et al. 1996. PubMed ID: 8673091). It has also been associated with autosomal recessive Fanconi anemia, complementation group D1 (OMIM #605724; Offit et al. 2003. PubMed ID: 14559878). This is a founder variant in the Ashkenazi Jewish population, identified in about 1.5% of Ashkenazi Jewish individuals unselected for breast cancer (Abeliovich et al. 1997. PubMed ID: 9042909; Roa et al. 1996. PubMed ID:8841191). This variant is frequently observed in the Ashkenazi Jewish population in gnomAD. This variant is also found in individuals of diverse ancestry at variable frequencies. It is interpreted as pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/9325/). In summary, this variant is interpreted as pathogenic. - |
Breast and/or ovarian cancer Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Mar 06, 2022 | - - |
BRCA2-related cancer predisposition Pathogenic:1
| Pathogenic, reviewed by expert panel | curation | ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel, ClinGen | Jun 11, 2024 | The c.5946del variant in BRCA2 is a deletion of a single nucleotide, predicted to encode a frameshift with consequent premature termination of the protein at codon 22 of the frameshift, or amino acid 2003 (p.Ser1982ArgfsTer22). This deletion variant was not observed in gnomAD v2.1 (exomes only, non-cancer subset) or gnomAD v3.1 (non-cancer subset), but PM2_Supporting was not applied since recall is suboptimal for this type of variant (PM2_Supporting not met). Frameshift variant predicted to cause a premature stop codon in biologically-relevant-exon 11 leading to nonsense mediated decay (PVS1 met). The ENIGMA BRCA1/2 VCEP considered multiple lines of functional and clinical evidence to define exon-specific weights for PTC in BRCA2, and results indicate that strong evidence towards pathogenicity may be applied for a PTC variant in BRCA2 exon 11 (PM5_Strong (PTC)). This variant has been detected in 6 individuals with phenotype consistent with BRCA2-Fanconi Anemia (FA). At least two clinical features of FA (physical features, pathology findings and cancer diagnosis <=5yr) and confirmed chromosome breakage, are seen in these individuals. 6 were compound heterozygous for the variant and a pathogenic or likely pathogenic variant, and confirmed to be in trans. Total points equated to 8 (PM3_Strong met; PMIDs: 14559878, 15516848, 16825431, 19530235). In summary, this variant meets the criteria to be classified as a Pathogenic variant for BRCA2-related cancer predisposition based on the ACMG/AMP criteria applied as specified by the ENIGMA BRCA1/2 VCEP (PVS1, PM5_Strong (PTC), PM3_Strong). - |
Fanconi anemia complementation group D1 Pathogenic:1
| Pathogenic, no assertion criteria provided | literature only | OMIM | Sep 12, 2016 | - - |
Breast neoplasm Pathogenic:1
| Pathogenic, criteria provided, single submitter | research | A.C.Camargo Cancer Center / LGBM, A.C.Camargo Cancer Center | - | - - |
Ovarian neoplasm Pathogenic:1
| Pathogenic, no assertion criteria provided | research | German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne | Dec 01, 2018 | - - |
Endometrial carcinoma Pathogenic:1
| Pathogenic, no assertion criteria provided | clinical testing | CZECANCA consortium | Feb 21, 2023 | - - |
Pancreatic cancer, susceptibility to, 2 Other:1
| risk factor, no assertion criteria provided | literature only | OMIM | Sep 12, 2016 | - - |
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 reported in multiple Invitae PIN participants. Variant interpreted as Pathogenic and reported most recently on 7/5/2018 by 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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