rs80359675
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong
The NM_000059.4(BRCA2):c.771_775del(p.Asn257LysfsTer17) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000868 in 1,612,574 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. T256T) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_000059.4 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
BRCA2 | NM_000059.4 | c.771_775del | p.Asn257LysfsTer17 | frameshift_variant | 9/27 | ENST00000380152.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BRCA2 | ENST00000380152.8 | c.771_775del | p.Asn257LysfsTer17 | frameshift_variant | 9/27 | 5 | NM_000059.4 | A2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152226Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000798 AC: 2AN: 250748Hom.: 0 AF XY: 0.00000738 AC XY: 1AN XY: 135542
GnomAD4 exome AF: 0.00000822 AC: 12AN: 1460348Hom.: 0 AF XY: 0.00000963 AC XY: 7AN XY: 726556
GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152226Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1AN XY: 74374
ClinVar
Submissions by phenotype
Breast-ovarian cancer, familial, susceptibility to, 2 Pathogenic:14
Pathogenic, no assertion criteria provided | clinical testing | Sharing Clinical Reports Project (SCRP) | Oct 09, 2012 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Jan 15, 2016 | - - |
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 | Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet | May 27, 2024 | PVS1; PM5_PTC_Strong - |
Pathogenic, criteria provided, single submitter | clinical testing | Department of Medical Genetics, Oslo University Hospital | Dec 19, 2016 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein | May 27, 2022 | ACMG classification criteria: PVS1 very strong, PS3 supporting, PS4 strong, PM2 moderated, PP1 strong - |
Pathogenic, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Sep 18, 2023 | This variant deletes 5 nucleotides in exon 9 of the BRCA2 gene, creating a frameshift and premature translation stop signal. This variant is also known as 999del5 and 995delCAAAT in the literature. This variant is expected to result in an absent protein product and transient expression of this variant protein in ex vivo cells showed that it was unstable (PMID: 15217494). This variant has been reported as an Iceland founder mutation where it segregates with female and male breast cancer in families (PMID: 8673089, 9150155). This variant is found to confer risk for breast cancer and ovarian cancer (PMID: 12114473, 15571962, 16768547). Haplotype analysis also suggests there are two common haplotypes for this variant in Finnish breast cancer affected families (PMID: 11781689). This variant also has been observed in breast and ovarian cancer affected individuals and families in Austria, Egypt, France and South Korea (PMID: 23877192, 24156927, 24549055, 25863477). This variant has been identified in 2/250748 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 | research | deCODE genetics, Amgen | Jul 21, 2023 | The variant NM_000059.4:c.771_775del (chr13:32331003) in BRCA2 was detected in 421 heterozygotes out of 58K WGS Icelanders (MAF= 0,363%). Following imputation in a set of 166K Icelanders (1,161 imputed heterozygotes) we observed an association with breast cancer using 6908 cases and 292623 controls (OR= 17.14, P= 1.37e-172). This variant has been reported in ClinVar previously as pathogenic. Based on ACMG criteria (PVS1, PS4, PP5) this variant classifies 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 | Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge | Oct 02, 2015 | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | May 01, 2000 | - - |
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 | BRCAlab, Lund University | Aug 26, 2022 | - - |
Hereditary breast ovarian cancer syndrome Pathogenic:5Other:1
Pathogenic, criteria provided, single submitter | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | - - |
not provided, no classification provided | literature only | GeneReviews | - | Founder variant in Icelanders - |
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 | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jul 06, 2023 | Variant summary: BRCA2 c.771_775delTCAAA (p.Asn257LysfsX17) 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. Variants downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 8e-06 in 250748 control chromosomes (gnomAD). c.771_775delTCAAA has been reported in the literature in multiple individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (examples: Johannesdottir_1996 and Ingvarsson_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 and demonstrated variant affects normal protein expression (example: Mikaelsdottir_2004). The following publications have been ascertained in the context of this evaluation (PMID: 9766673, 8706004, 15217494). Eighteen submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine | Sep 03, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 18, 2024 | This sequence change creates a premature translational stop signal (p.Asn257Lysfs*17) 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 (rs80359671, gnomAD 0.009%). This premature translational stop signal has been observed in individual(s) with breast and ovarian cancer (PMID: 8589730, 8673089, 9150155, 24549055, 25863477). It is commonly reported in individuals of Icelandic ancestry (PMID: 8673089, 9150155). This variant is also known as 999del5. ClinVar contains an entry for this variant (Variation ID: 9326). For these reasons, this variant has been classified as Pathogenic. - |
not provided Pathogenic:5
Pathogenic, criteria provided, single submitter | clinical testing | Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden | Nov 03, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Clinical Genetics and Genomics, Karolinska University Hospital | Dec 09, 2015 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Jul 31, 2024 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Sep 29, 2020 | This frameshift variant alters the translational reading frame of the BRCA2 mRNA and causes the premature termination of BRCA2 protein synthesis. In the published literature, the variant has been reported in individuals affected with breast cancer and has been described as a pathogenic founder variant in the Icelandic population (PMIDs: 31957001 (2020), 30093976 (2018), 23857704 (2013), and 17591843 (2007)). The frequency of this variant in the general population, 0.000092 (2/21636 chromosomes, http://gnomad.broadinstitute.org), is consistent with pathogenicity. Based on the available information, this variant is classified as pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Aug 01, 2023 | 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: shown in expression studies to be extremely unstable and to impact cytokinesis (Mikaelsdottir et al., 2004; Jonsdottir et al., 2009); Reported as a founder pathogenic variant in Iceland, accounting for 7-8% of all breast and ovarian cancer in the country (Johannesdottir et al., 1996; Thorlacius et al., 1997; Jonsdottir et al., 2009); Observed in individuals with a personal or family history consistent with pathogenic variants in this gene (Tavtigian et al., 1996; Thorlacius et al., 1997; Azzollini et al., 2017; Chan et al., 2018; Bhaskaran et al., 2019); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Not observed at significant frequency in large population cohorts (gnomAD); Also known as 999_1003del; This variant is associated with the following publications: (PMID: 28199346, 23857704, 8589730, 19478387, 8706004, 23747895, 9150155, 27537391, 28235830, 27062684, 29339979, 10807692, 30720243, 30702160, 30093976, 31159747, 31957001, 29625052, 26689913, 30787465, 31723001, 30350268, 31825140, 34254208, 32341426, 9802270, 30875412, 15571962, 34645131, 15217494) - |
Familial cancer of breast Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Nov 24, 2023 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneKor MSA | Jan 01, 2020 | This is a deletion of five base pairs, which results in frameshift and creation of a novel stop codon 17 amino acid residues later. The result is a truncated, non-functional protein. Truncating variants in BRCA2 are known to be pathogenic.This variant is also known as 999del5 in the literature and is a common cause of breast and ovarian cancer in the Icelandic population but has been reported also in individuals of other ethnicities (PMID: 9150155, 8673089, 8589730 ; 25863477 ).The mutation database Clinvar contains entries for this variant (Variation ID:9326). - |
Hereditary cancer-predisposing syndrome Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Jun 01, 2023 | This variant deletes 5 nucleotides in exon 9 of the BRCA2 gene, creating a frameshift and premature translation stop signal. This variant is also known as 999del5 and 995delCAAAT in the literature. This variant is expected to result in an absent protein product and transient expression of this variant protein in ex vivo cells showed that it was unstable (PMID: 15217494). This variant has been reported as an Iceland founder mutation where it segregates with female and male breast cancer in families (PMID: 8673089, 9150155). This variant is found to confer risk for breast cancer and ovarian cancer (PMID: 12114473, 15571962, 16768547). Haplotype analysis also suggests there are two common haplotypes for this variant in Finnish breast cancer affected families (PMID: 11781689). This variant also has been observed in breast and ovarian cancer affected individuals and families in Austria, Egypt, France and South Korea (PMID: 23877192, 24156927, 24549055, 25863477). This variant has been identified in 2/250748 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, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 12, 2024 | The c.771_775delTCAAA (p.N257Kfs*17) alteration, located in exon 9 (coding exon 8) of the BRCA2 gene, consists of a deletion of 5 nucleotides from position 771 to 775, causing a translational frameshift with a predicted alternate stop codon after 17 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% (2/250748) total alleles studied. The highest observed frequency was <0.001% (2/21636) of alleles. This alteration has been reported in several individuals diagnosed with breast and/or ovarian cancer (Tavtigian, 1996; Tryggvadottir, 2013; Azzollini, 2016; Sun, 2017). This mutation has been described as an Icelandic founder mutation accounting for 7-8% of female breast cancer and 40% of male breast cancer in Iceland (Thorlacius, 1997; Mikaelsdottir, 2004). One Icelandic study comparing breast cancer patients with and without this mutation suggests that estrogen receptor status in carrier individuals is a factor affecting prognosis (Jonasson, 2016). Of note, this alteration is also designated as 999del5 in published literature. Based on the available evidence, this alteration is classified as pathogenic. - |
Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Department of Molecular Diagnostics, Institute of Oncology Ljubljana | Apr 02, 2020 | - - |
Breast carcinoma Pathogenic:1
Pathogenic, no assertion criteria provided | clinical testing | Medical Genetics Laboratory, Umraniye Training and Research Hospital, University of Health Sciences | Aug 08, 2021 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at