13-32338633-AT-ATT
Variant summary
Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong
The NM_000059.4(BRCA2):c.4284dupT(p.Gln1429SerfsTer9) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000118 in 1,446,458 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
Consequence
NM_000059.4 frameshift
Scores
Clinical Significance
Conservation
Publications
- breast-ovarian cancer, familial, susceptibility to, 2Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), ClinGen
- Fanconi anemia complementation group D1Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, ClinGen, G2P
- pancreatic cancer, susceptibility to, 2Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
- sarcomaInheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
- hereditary breast ovarian cancer syndromeInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- Fanconi anemiaInheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
- medulloblastomaInheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
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ACMG classification
Our verdict: Pathogenic. The variant received 16 ACMG points.
Variant Effect in Transcripts
ACMG analysis was done for transcript: NM_000059.4. You can select a different transcript below to see updated ACMG assignments.
RefSeq Transcripts
| Selected | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| BRCA2 | NM_000059.4 | MANE Select | c.4284dupT | p.Gln1429SerfsTer9 | frameshift | Exon 11 of 27 | NP_000050.3 | ||
| BRCA2 | NM_001432077.1 | c.4284dupT | p.Gln1429SerfsTer9 | frameshift | Exon 11 of 27 | NP_001419006.1 | |||
| BRCA2 | NM_001406720.1 | c.4284dupT | p.Gln1429SerfsTer9 | frameshift | Exon 11 of 27 | NP_001393649.1 |
Ensembl Transcripts
| Selected | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| BRCA2 | ENST00000380152.8 | TSL:5 MANE Select | c.4284dupT | p.Gln1429SerfsTer9 | frameshift | Exon 11 of 27 | ENSP00000369497.3 | ||
| BRCA2 | ENST00000544455.6 | TSL:1 | c.4284dupT | p.Gln1429SerfsTer9 | frameshift | Exon 11 of 27 | ENSP00000439902.1 | ||
| BRCA2 | ENST00000530893.7 | TSL:1 | c.3915dupT | p.Gln1306SerfsTer9 | frameshift | Exon 11 of 27 | ENSP00000499438.2 |
Frequencies
GnomAD3 genomes
GnomAD2 exomes AF: 0.00000409 AC: 1AN: 244426 AF XY: 0.00 show subpopulations
GnomAD4 exome AF: 0.0000118 AC: 17AN: 1446458Hom.: 0 Cov.: 35 AF XY: 0.00000977 AC XY: 7AN XY: 716644 show subpopulations
Age Distribution
GnomAD4 genome
ClinVar
Submissions by phenotype
Breast-ovarian cancer, familial, susceptibility to, 2 Pathogenic:11
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.
Variant allele predicted to encode a truncated non-functional protein.
ACMG criteria used to clasify this variant: PVS1, PS4, PM1, PM2, PP5
This c.4284_4285insT (p.Gln1429Serfs*9) variant in the BRCA2 gene has been reported in multiple breast cancer and ovarian cancer patient [PMID: 21120943, 22085629, 24728189] while only observed once in general population according to gnomad database. This variant is predicted to cause loss of function of normal protein through mRNA decay or producing a truncated protein, which is a known disease mechanism for this gene. Based on the current evidences, this c.4284_4285insT (p.Gln1429Serfs*9) variant in the BRCA2 gene is classified as pathogenic.
The heterozygous c.4284dup (p.Gln1429SerfsTer9) variant identified in exon 11 (of 27) of the BRCA2 gene alters the wild-type translational reading frame and is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. This variant has been previously reported in multiple unrelated individuals affected with BRCA2-associated disorders [PMID: 11179017;PMID: 26360800;PMID: 28657667;PMID: 29753700]. This variant has also been reported as pathogenic in the ClinVar database by multiple independent laboratories (Variation ID: 37892). The variant is absent from the gnomAD(v3) database indicating it is an extremely rare allele in the populations represented in that database. Based on the available evidence, the heterozygous c.4284dup (p.Gln1429SerfsTer9) variant identified in the BRCA2 gene is reported as Pathogenic.
BRCA2 (p.Gln1429fs): This insertion of one nucleotide in BRCA2 is denoted c.4284insT at the cDNA level and p.Gln1429SerfsX9 (Q1429SfsX9) at the protein level. The normal sequence, with the base that is duplicated in brackets, is ATTTTT[insT]CAGA. The duplication causes a frameshift, which changes a Glutamine to a Serine at codon 1429 and creates a premature stop codon at position 9 of the new reading frame. This variant is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. BRCA2 c.4284insT, previously reported as 4510dupT or 4512dupT using alternate nomenclature. The BRCA2 c.4284insT; p.Gln1429fs variant is reported in the literature in multiple individuals affected with breast or ovarian cancer or that met criteria for hereditary breast and/or ovarian cancer (HBOC) syndrome (Fernandes 2016, Koumpis 2011, Palmero 2018, Risch 2001, Zhang 2011, Zuradelli 2010). This variant is present on a single chromosome in the Genome Aggregation Database, indicating it is not a common polymorphism, and it is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 37892). This variant causes a frameshift by inserting 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.
Hereditary breast ovarian cancer syndrome Pathogenic:7
This sequence change creates a premature translational stop signal (p.Gln1429Serfs*9) 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 (rs80359439, gnomAD 0.007%). This premature translational stop signal has been observed in individual(s) with breast and ovarian cancer (PMID: 11179017, 20373018, 22085629, 24156927, 24728189). This variant is also known as 4510insT and 4512insT. ClinVar contains an entry for this variant (Variation ID: 37892). For these reasons, this variant has been classified as Pathogenic.
Variant summary: BRCA2 c.4284dupT (p.Gln1429SerfsX9) 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 4e-06 in 247482 control chromosomes (gnomAD). c.4284dupT has been reported in the literature in multiple individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (e.g. Risch_2001, Caux-Moncoutier_2011, Song_2014, Tea_2014, Fernandes_2016). These data indicate that the variant is very likely to be associated with disease. Thirteen clinical diagnostic laboratories and one expert panel (ENIGMA) have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
This variant is a duplication of T at nucleotide position 4284 in exon 11 of the BRCA2 mRNA c.(4284dupT), causing a frameshift after codon 1429 and the creation of a premature translation stop signal 9 amino acid residues later, p.(Gln1429Serfs*9). This is expected to result in an absent or disrupted protein product. Truncating variants in BRCA2 are known to be pathogenic (PMID:20104584). This variant is not present in population databases (rs80359439). ClinVar contains entries for this variant where it is listed as pathogenic (VCV000037892.116). Based on the classification criteria set by the ACMG and AMP (PMID:25741868) this variant has been classified as pathogenic.
The frameshift duplication NM_000059.4(BRCA2):c.4284dupT (p.Gln1429Serfs*9) has been reported to ClinVar as Pathogenic with a status of (3 stars) reviewed by expert panel (Variation ID 37892 as of 2025-01-02). This variant is predicted to cause loss of normal protein function through protein truncation caused a frameshift mutation. This variant is a frameshift variant which occurs in an exon of BRCA2 upstream of where nonsense mediated decay is predicted to occur. This variant has been previously classified as pathogenic, indicating that the region is critical to protein function. The p.Gln1429Serfs*9 variant is a loss of function variant in the gene BRCA2, which is intolerant of Loss of Function variants, as indicated by the presence of existing pathogenic loss of function variant NP_000050.3:p.M1Lfs*44 and 4557 others. For these reasons, this variant has been classified as Pathogenic.
The p.Gln1429SerfsX9 variant in BRCA2 has been reported in >10 individuals with BRCA2-associated cancers (Risch 2001 PMID:11179017, Zuradelli 2010 PMID:20373018, Zhang 2011 PMID:21324516, Koumpis 2011 PMID:22085629, Caux-Moncoutier 2011 PMID:21120943, Song 2014 PMID:24728189, Pilie 2017 PMID:28657667, Nielsen 2016 PMID:26360800, Palmero 2018 PMID:29907814, Waszak 2018 PMID:29753700, Breast Cancer Information Core (BIC) database: https://research.nhgri.nih.gov/bic/). It was absent from large population studies. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 1429 and leads to a premature termination codon 9 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 hereditary breast and ovarian cancer (HBOC). Additionally, this variant was classified as pathogenic on Sept 13, 2016 by the ClinGen-approved ENIGMA expert panel (Variation ID 37892). In summary, this variant meets criteria to be classified as pathogenic for HBOC in an autosomal dominant manner. ACMG/AMP Criteria Applied: PS4_Moderate, PM2_Supporting, PVS1.
not provided Pathogenic:6
BRCA2: PVS1, PS4:Moderate, PM2:Supporting
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; Not observed at significant frequency in large population cohorts (gnomAD); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Also known as 4512dupT; This variant is associated with the following publications: (PMID: 21120943, 27836010, 22085629, 24728189, 22762150, 24156927, 24670361, 20373018, 11179017, 27741520, 29061375, 28657667, 29907814, 26360800, 29753700, 21324516, 21702907, 23942203, 30128899, 29641532, 29084914, 30720243, 31368036, 31336956, 29483665, 31447099, 32846166, 32295079, 32438681, 32719484, 32853339, 32782288, 28888541, 36988593, 36329109, 37179432, 36136896, 35205366, 35463374, 35216584)
The BRCA2 c.4284dup (p.Gln1429Serfs*9) variant (also known as 4512insT) 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 individuals with breast/ovarian cancer (PMIDs: 32846166 (2020), 27741520 (2016), 21120943 (2011), 22085629 (2011), 11179017 (2001)) and prostate cancer (PMID: 28657667 (2017)). The frequency of this variant in the general population, 0.0000041 (1/244426 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is consistent with pathogenicity. Based on the available information, this variant is classified as pathogenic.
The BRCA2 c.4284dupT; p.Gln1429SerfsTer9 variant (rs1005805156), also known as c.4512dup, is reported in the literature in multiple individuals affected with breast or ovarian cancer or that met criteria for hereditary breast and/or ovarian cancer (HBOC) syndrome (Fernandes 2016, Koumpis 2011, Palmero 2018, Risch 2001, Zhang 2011, Zuradelli 2010). This variant is present on a single chromosome in the Genome Aggregation Database, indicating it is not a common polymorphism, and it is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 37892). This variant causes a frameshift by inserting 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. References: Fernandes GC et al. Prevalence of BRCA1/BRCA2 mutations in a Brazilian population sample at-risk for hereditary breast cancer and characterization of its genetic ancestry. Oncotarget. 2016 Dec 6;7(49):80465-80481. Koumpis C et al. Prevalence of BRCA1 and BRCA2 mutations in unselected breast cancer patients from Greece. Hered Cancer Clin Pract. 2011 Nov 15;9:10. Palmero EI et al. The germline mutational landscape of BRCA1 and BRCA2 in Brazil. Sci Rep. 2018 Jun 15;8(1):9188. Risch HA et al. Prevalence and penetrance of germline BRCA1 and BRCA2 mutations in a population series of 649 women with ovarian cancer. Am J Hum Genet. 2001 Mar;68(3):700-10. 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. Zuradelli M et al. Four new cases of double heterozygosity for BRCA1 and BRCA2 gene mutations: clinical, pathological, and family characteristics. Breast Cancer Res Treat. 2010 Nov;124(1):251-8.
PVS1, PS4_Mod, PM1, PM2, PP5
Familial cancer of breast Pathogenic:2
Criteria applied: PVS1,PM5_STR
Hereditary cancer-predisposing syndrome Pathogenic:2
This variant inserts 1 nucleotide 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 has been reported in at least 10 individuals affected with breast and ovarian cancer (PMID: 11179017, 21324516, 22085629, 24728189, 27741520, 29084914, 30128899, 33471991; Leiden Open Variation Database DB-ID BRCA2_001668) and in suspected hereditary breast and ovarian cancer families (PMID: 21120943, 24156927, 29483665). This variant also has been reported in an individual affected with prostate cancer with multiple primary malignancies and another individual affected with medulloblastoma (PMID: 28657667, 29753700). This variant has been identified in 1/244426 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.
The c.4284dupT pathogenic mutation, located in coding exon 10 of the BRCA2 gene, results from a duplication of T at nucleotide position 4284, causing a translational frameshift with a predicted alternate stop codon (p.Q1429Sfs*9). This mutation has been reported in multiple individuals diagnosed with breast and/or ovarian cancer (Risch HA et al. Am. J. Hum. Genet. 2001 Mar;68:700-10; Koumpis C et al. Hered Cancer Clin Pract. 2011;9:10; Zhang S et al. Gynecol. Oncol. 2011 May;121:353-7; Fernandes GC et al. Oncotarget. 2016 Dec;7:80465-80481; Labidi-Galy SI et al. Clin. Cancer Res. 2018 01;24:326-333; Marchetti C et al. Ann. Surg. Oncol. 2018 Nov;25:3701-3708; Rebbeck TR et al. Hum. Mutat. 2018 05;39:593-620), an individual with prostate cancer (Pilie PG et al. Cancer. 2017 Oct;123(20):3925-3932), and one individual with medulloblastoma diagnosed in infancy (Waszak SM et al. Lancet Oncol. 2018 06;19:785-798). Of note, this alteration is also designated as 4512insT and 4510insT 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:1
BRCA2-related cancer predisposition Pathogenic:1
This variant inserts 1 nucleotide 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 has been reported in at least 10 individuals affected with breast and ovarian cancer (PMID: 11179017, 21324516, 22085629, 24728189, 27741520, 29084914, 30128899, 33471991; Leiden Open Variation Database DB-ID BRCA2_001668) and in suspected hereditary breast and ovarian cancer families (PMID: 21120943, 24156927, 29483665). This variant also has been reported in an individual affected with prostate cancer with multiple primary malignancies and another individual affected with medulloblastoma (PMID: 28657667, 29753700). This variant has been identified in 1/244426 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.
Gastric cancer Pathogenic:1
Inherited ovarian cancer (without breast cancer) Pathogenic:1
PS4_strong, PM2_supporting, PVS1_very-strong, PM5_strong
Inherited prostate cancer Pathogenic:1
PS4_strong, PM2_supporting, PVS1_very-strong, PM5_strong
Medulloblastoma;C0346153:Familial cancer of breast;C0376358:Prostate cancer;C1838457:Fanconi anemia complementation group D1;C2675520:Breast-ovarian cancer, familial, susceptibility to, 2;C2751641:Glioma susceptibility 3;C3150546:Pancreatic cancer, susceptibility to, 2;CN033288:Wilms tumor 1 Pathogenic:1
BRCA2-related disorder Pathogenic:1
The BRCA2 c.4284dupT variant is predicted to result in a frameshift and premature protein termination (p.Gln1429Serfs*9). This variant (also known as 4512dupT and 4510insT) has been frequently reported in the literature as pathogenic in individuals with a personal and/or family history of breast and ovarian cancer (see, for example, Table 1, Risch et al. 2001. PubMed ID: 11179017; Zuradelli et al. 2010. PubMed ID: 20373018; Table 1, Fernandes et al. 2016. PubMed ID: 27741520). This variant is reported in 0.00090% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/13-32912770-A-AT). In ClinVar, this variant has been reviewed by an expert panel and is interpreted as pathogenic by numerous laboratories (https://www.ncbi.nlm.nih.gov/clinvar/variation/37892/). Truncating variants in BRCA2 are expected to be pathogenic. This variant is interpreted as pathogenic.
Malignant tumor of breast Pathogenic:1
The BRCA2 p.Gln1429SerfsX9 variant was identified in 3 of 4408 proband chromosomes (frequency: 0.001) from individuals or families with breast and ovarian cancers (Caux-Moncoutier 2011, Risch 2001, Terabeax 2014). The variant was identified by our laboratory in 1 individual who was unaffected at the time of testing. The variant was also identified in dbSNP (ID: rs80359439 “With pathogenic allele”. The p.Gln1429SerfsX9variant was identified in the Clinvar database and classified as pathogenic by Invitae, Ambry Genetics, GeneDx, BIC and Sharing clinical Reports project. Counsy classified the variant as likely pathogenic. In the BRCA Share UMD database, the variant was identified 14x and classified as causal. The variant was identified with a co-occurring pathogenic BRCA1 variant (c.5266dup (p.Gln1756ProfsX74). The BIC database identified the variant 4X with clinical importance and classified as pathogenic. The ARUP laboratory identified the variant 1x and classified it as pathogenic. The p.Gln1429SerfsX9 duplication variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 1429 and leads to a premature stop codon 9 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.
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at