rs80359499
Variant summary
Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000059.4(BRCA2):c.5238dupT(p.Asn1747fs) variant causes a frameshift, stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000206 in 1,458,548 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, stop_gained
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 18 ACMG points.
Transcripts
RefSeq
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| BRCA2 | ENST00000380152.8 | c.5238dupT | p.Asn1747fs | frameshift_variant, stop_gained | Exon 11 of 27 | 5 | NM_000059.4 | ENSP00000369497.3 | ||
| BRCA2 | ENST00000530893.7 | c.4869dupT | p.Asn1624fs | frameshift_variant, stop_gained | Exon 11 of 27 | 1 | ENSP00000499438.2 | |||
| BRCA2 | ENST00000614259.2 | n.5238dupT | non_coding_transcript_exon_variant | Exon 10 of 26 | 2 | ENSP00000506251.1 |
Frequencies
GnomAD3 genomes
GnomAD4 exome AF: 0.00000206 AC: 3AN: 1458548Hom.: 0 Cov.: 43 AF XY: 0.00000276 AC XY: 2AN XY: 725606 show subpopulations
Age Distribution
GnomAD4 genome
ClinVar
Submissions by phenotype
not provided Pathogenic:11
This frameshift variant causes the premature termination of BRCA2 protein synthesis. It also has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In addition, it has been described in individuals with breast cancer and ovarian cancer (PMID: 26681312 (2015), 25682074 (2015), 25186627 (2015), 24728189 (2014), 22430266 (2012)). Based on the available information, this variant is classified as pathogenic. -
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Nonsense 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; Reported in association with hereditary breast and/or ovarian cancer (Frank 1998, Meindl 2002, Nanda 2005, Pohlreich 2005, van der Hout 2006, Song 2014, Wong-Brown 2015, Frey 2017); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Not observed in large population cohorts (Lek 2016); This variant is associated with the following publications: (PMID: 24504028, 24728189, 26681312, 27856273, 28495237, 28324225, 32295079, 16168118, 18703817, 22430266, 16234499, 15131399, 16683254, 9667259, 23110154, 27157322, 25682074, 11802209, 28454591, 27930734, 26022348, 30702160, 32719484) -
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PVS1, PM2, PP5 -
BRCA2: PVS1, PM2, PS4:Moderate -
Breast-ovarian cancer, familial, susceptibility to, 2 Pathogenic:8Other:1
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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. -
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Variant allele predicted to encode a truncated non-functional protein. -
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PVS1; PM2_supporting; PM5_PTC_Strong -
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Hereditary breast ovarian cancer syndrome Pathogenic:5
Variant summary: BRCA2 c.5238dupT (p.Asn1747X) 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 was absent in 252034 control chromosomes. c.5238dupT has been reported in the literature in multiple individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (example, Meindl_2002, Nanda_2005, Palma_2008, Pern_2012, Pohlreich_2005, Song_2014). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Multiple clinical diagnostic laboratories and an expert panel (ENIGMA) have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
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This sequence change creates a premature translational stop signal (p.Asn1747*) 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 not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with breast and/or ovarian cancer (PMID: 11802209, 16168118, 23110154, 25682074, 26681312). This variant is also known as 5466insT. ClinVar contains an entry for this variant (Variation ID: 37954). For these reasons, this variant has been classified as Pathogenic. -
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Hereditary cancer-predisposing syndrome Pathogenic:3
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 eight individuals affected with breast or ovarian cancer and additional suspected hereditary breast and ovarian cancer families (PMID: 9667259, 11802209, 16168118, 16234499, 18703817, 23110154, 24504028, 24728189, 25186627, 25682074, 26681312). This variant has not been identified 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. -
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The c.5238dupT pathogenic mutation (also known as p.N1747*), located in coding exon 10 of the BRCA2 gene, results from a duplication of T at nucleotide position 5238. This changes the amino acid from a asparagine to a stop codon within coding exon 10. This mutation has been described in multiple breast and/or ovarian cancer families, including individuals with pre-menopausal and triple negative breast cancer (Frank TS et al. J. Clin. Oncol. 1998 Jul;16(7):2417-25; Meindl A et al. Int. J. Cancer. 2002 Feb;97(4):472-80; Pohlreich P et al. Breast Cancer Res. 2005 Jul;7(5):R728-36; Palma MD et al. Cancer Res. 2008 Sep;68(17):7006-14; Pern F et al. PLoS One. 2012 Oct;7(10):e47993; Wong-Brown MW et al. Breast Cancer Res. Treat. 2015 Feb;150:71-80; Schroeder C et al. Breast Cancer Res. Treat. 2015 Jul;152:129-136). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Of note, this alteration is also designated as 5466insT 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
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Familial cancer of breast Pathogenic:2
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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
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Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:1
Criteria applied: PVS1,PM5_STR,PM2_SUP -
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 eight individuals affected with breast or ovarian cancer and additional suspected hereditary breast and ovarian cancer families (PMID: 9667259, 11802209, 16168118, 16234499, 18703817, 23110154, 24504028, 24728189, 25186627, 25682074, 26681312). This variant has not been identified 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. -
BRCA2-related disorder Pathogenic:1
The BRCA2 c.5238dupT variant is predicted to result in premature protein termination (p.Asn1747*). This variant has been documented to be pathogenic in multiple unrelated individuals with breast or ovarian cancer [Reported in Table III as 5466insT(1747X) in Meindl et al. 2002. PubMed ID: 11802209; reported as c.5238insT in Pern et al. 2012. PubMed ID: 23110154; reported in Table S1 as S1746fs in Cunningham et al. 2014. PubMed ID: 24504028; reported in Suppl Table 1 as c.5237_5238insT (p.S1746fs) in Schroeder et al. 2015. PubMed ID: 26022348]. This variant has not been reported in a large population database, indicating this variant is rare. It is interpreted as pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/37954/). Nonsense variants in BRCA2 are expected to be pathogenic. This variant is interpreted as pathogenic. -
Malignant tumor of breast Pathogenic:1
The BRCA2 p.Asn1747X variant was identified in 3 of 1936 proband chromosomes (frequency: 0.002) from German and Czech individuals or families with breast/ovarian or triple negative breast cancers (Meindl 2002, Pohlreich 2005, Pern 2012). The variant was also identified in dbSNP (ID: rs80359499) “With Pathogenic allele”, but no frequency information was provided, thus the prevalence of this variant in the general population could not be determined. The variant was identified in HGMD, the BIC database (9X with pathogenic clinical importance), and in Clinvitae (3x), the ClinVar database by multiple submitters (the Sharing Clinical Reports Project (SCRP) (submitted within the ClinVar database and derived from Myriad reports) as a pathogenic variant, 2X by BIC (both somatic and germline) classification not provided, Invitae, classification not provided, classified as pathogenic by Ambry Genetics, GeneDX and Molecular Diagnostic Laboratory - CHEO ). The c.5238 duplication variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 1747 and leads to a premature stop codon at position 1747. 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