rs80359616
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000059.4(BRCA2):c.6644_6647del(p.Tyr2215SerfsTer13) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000124 in 1,612,198 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★★). Synonymous variant affecting the same amino acid position (i.e. Y2215Y) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_000059.4 frameshift
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
BRCA2 | NM_000059.4 | c.6644_6647del | p.Tyr2215SerfsTer13 | frameshift_variant | 11/27 | ENST00000380152.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BRCA2 | ENST00000380152.8 | c.6644_6647del | p.Tyr2215SerfsTer13 | frameshift_variant | 11/27 | 5 | NM_000059.4 | A2 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152244Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000401 AC: 1AN: 249524Hom.: 0 AF XY: 0.00000742 AC XY: 1AN XY: 134852
GnomAD4 exome AF: 6.85e-7 AC: 1AN: 1459954Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 726116
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152244Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1AN XY: 74388
ClinVar
Submissions by phenotype
Breast-ovarian cancer, familial, susceptibility to, 2 Pathogenic:8
Pathogenic, reviewed by expert panel | curation | Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) | Sep 08, 2016 | Variant allele predicted to encode a truncated non-functional protein. - |
Pathogenic, no assertion criteria provided | clinical testing | Sharing Clinical Reports Project (SCRP) | May 01, 2012 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Apr 18, 2017 | - - |
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, criteria provided, single submitter | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | Sep 21, 2015 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Dec 13, 2023 | This variant deletes 4 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 6872del4 in the literature. This variant has been reported in individuals with a personal and/or family history of breast, ovarian cancer, or pancreatic cancer (PMID: 9150172, 11179017, 11179017, 11597388, 16683254, 18284688, 21324516, 29084914, 29446198, 29625052, 29922827). This variant has been identified in 1/249524 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of BRCA2 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. - |
Pathogenic, no assertion criteria provided | clinical testing | Breast Cancer Information Core (BIC) (BRCA2) | May 29, 2002 | - - |
Pathogenic, no assertion criteria provided | clinical testing | BRCAlab, Lund University | Mar 02, 2020 | - - |
not provided Pathogenic:6
Pathogenic, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Mar 16, 2020 | PVS1, PM2, PP5 - |
Pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | May 21, 2020 | The BRCA2 c.6644_6647delACTC; p.Tyr2215fs variant (rs80359616), also known as c.6872del4, is reported in the literature in several individuals with breast and/or ovarian cancer (Caputo 2012, Serova-Sinilnikova 1997, Zhang 2011). This variant is also reported in ClinVar (Variation ID: 38060). It is only observed on one allele in the Genome Aggregation Database, indicating it is not a common polymorphism. This variant causes a frameshift by deleting four nucleotides, 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 Caputo S et al. Description and analysis of genetic variants in French hereditary breast and ovarian cancer families recorded in the UMD-BRCA1/BRCA2 databases. Nucleic Acids Res. 2012;40(Database issue):D992-1002. Serova-Sinilnikova OM et al. BRCA2 mutations in hereditary breast and ovarian cancer in France. Am J Hum Genet. 1997 May;60(5):1236-9. Zhang S et al. Frequencies of BRCA1 and BRCA2 mutations among 1,342 unselected patients with invasive ovarian cancer. Gynecol Oncol. 2011;121(2):353-7. - |
Pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen | Oct 23, 2020 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jan 19, 2021 | 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; Observed in individuals with a personal and/or family history of breast and/or ovarian cancer (Serova-Sinilnikova 1997, Verhoog 1999, Risch 2001, Verhoog 2001, Lewis 2006, Zhang 2011, Caputo 2012, Tung 2015, Johnson 2017, Labidi-Galy 2018); Not observed at a significant frequency in large population cohorts (Lek 2016); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Also known as 6872_6875delACTC; This variant is associated with the following publications: (PMID: 11179017, 29625052, 9150172, 16683254, 21324516, 22144684, 26586665, 26926684, 16541310, 22019625, 11597388, 21120943, 25186627, 28526081, 28476184, 15131399, 29084914, 10550133, 30720243) - |
Pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Nov 26, 2019 | This frameshift variant causes the premature termination of BRCA2 protein synthesis. In addition, it has been seen in affected individuals with ovarian cancer in the published literature (PMIDs: 21324516 (2011), 22144684 (2012), 29084914 (2018), and 30720243 (2019)). Based on the available information, this variant is classified as pathogenic. - |
Hereditary breast ovarian cancer syndrome Pathogenic:4
Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jan 27, 2017 | The p.Tyr2215fs variant in BRCA2 has been reported in >25 individuals with BRCA2 -associated cancers and segregated with disease in 5 relatives from 2 families ( Serova-Sinilnikova 1997, Caputo 2012, Zhang 2011, Risch 2001, Verhoog 2001, and Breast Cancer Information Core (BIC) database). It was also absent from large po pulation studies. This variant is predicted to cause a frameshift, which alters the protein?s amino acid sequence beginning at position 2215 and leads to a prem ature termination codon 13 amino acids downstream. This alteration is then predi cted 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 ovar ian cancer (HBOC). In addition, this variant was classified as Pathogenic on Sep tember 8, 2016 by the ClinGen-approved ENIGMA expert panel (ClinVar SCV000301085 .2). In summary, this variant meets criteria to be classified as pathogenic for HBOC in an autosomal dominant manner. - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 27, 2023 | This sequence change creates a premature translational stop signal (p.Tyr2215Serfs*13) 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 (rs80359616, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with breast and/or ovarian cancer (PMID: 9150172, 16683254, 21120943, 21324516, 22144684). This variant is also known as 6872del4 or 6872delACTC. ClinVar contains an entry for this variant (Variation ID: 38060). For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Mar 05, 2019 | Variant summary: The variant, BRCA2 c.6644_6647delACTC (p.Tyr2215SerfsX13) 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 (eg. c.6682dupG(p.Val2228fsX5), c.6757_6758delCT(p.Leu2253fsX7)). The variant allele was found at a frequency of 4.1e-06 in 244534 control chromosomes (gnomAD) and has been reported in the literature in multiple individuals affected with breast cancer, ovarian cancer and pancreatic cancer (Caputo_2012, Lee_2008, Hu_2018, Zhang_2011). 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. Ten ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Pathogenic, no assertion criteria provided | research | Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto | Jan 31, 2014 | - - |
Hereditary cancer-predisposing syndrome Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Apr 02, 2024 | The c.6644_6647delACTC pathogenic mutation, located in coding exon 10 of the BRCA2 gene, results from a deletion of 4 nucleotides at nucleotide positions 6644 to 6647, causing a translational frameshift with a predicted alternate stop codon (p.Y2215Sfs*13). This mutation has been reported in numerous individuals diagnosed with hereditary breast and ovarian cancer (HBOC) syndrome (Serova-Sinilnikova OM et al. Am. J. Hum. Genet., 1997 May;60:1236-9; Verhoog LC et al. J. Clin. Oncol., 1999 Nov;17:3396-402; Risch HA et al. Am J Hum Genet, 2001 Mar;68:700-10; van der Hout AH et al. Hum Mutat, 2006 Jul;27:654-66; Lewis CM et al. Breast Cancer Res Treat, 2006 Sep;99:103-15; Coulet F et al. Genet Test Mol Biomarkers, 2010 Oct;14:677-90; Zhang S et al. Gynecol Oncol, 2011 May;121:353-7; Caux-Moncoutier V et al. Hum Mutat, 2011 Mar;32:325-34; Caputo S et al. Nucleic Acids Res, 2012 Jan;40:D992-1002; Lecarpentier J et al. Breast Cancer Res, 2012 Jul;14:R99; Labidi-Galy SI et al. Clin Cancer Res, 2018 01;24:326-333). This mutation has also been reported in multiple individuals with pancreatic cancer (Huang KL et al. Cell, 2018 04;173:355-370.e14; Hu C et al. JAMA, 2018 06;319:2401-2409). Of note, this alteration is also designated as 6872del4 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. - |
Pathogenic, criteria provided, single submitter | curation | Sema4, Sema4 | Jun 16, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Aug 28, 2023 | This variant deletes 4 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 6872del4 in the literature. This variant has been reported in individuals with a personal and/or family history of breast, ovarian cancer, or pancreatic cancer (PMID: 9150172, 11179017, 11179017, 11597388, 16683254, 18284688, 21324516, 29084914, 29446198, 29625052, 29922827). This variant has been identified in 1/249524 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. - |
Breast and/or ovarian cancer Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | May 26, 2017 | - - |
Familial cancer of breast Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Feb 16, 2024 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at