rs80359395
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong
The NM_000059.4(BRCA2):c.3680_3681del(p.Leu1227GlnfsTer5) variant causes a frameshift change. The variant allele was found at a frequency of 0.0000186 in 1,611,868 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. L1227L) 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.3680_3681del | p.Leu1227GlnfsTer5 | frameshift_variant | 11/27 | ENST00000380152.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BRCA2 | ENST00000380152.8 | c.3680_3681del | p.Leu1227GlnfsTer5 | frameshift_variant | 11/27 | 5 | NM_000059.4 | A2 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152136Hom.: 0 Cov.: 32
GnomAD4 exome AF: 0.0000199 AC: 29AN: 1459732Hom.: 0 AF XY: 0.0000179 AC XY: 13AN XY: 725926
GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152136Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74320
ClinVar
Submissions by phenotype
Breast-ovarian cancer, familial, susceptibility to, 2 Pathogenic:8
Pathogenic, criteria provided, single submitter | clinical testing | Genetics and Molecular Pathology, SA Pathology | Jan 20, 2021 | BRCA2:c.3680_3681delTG is classified as PATHOGENIC (ENIGMA criteria 2017) BRCA2:c.3680_3681delTG is a deletion of two consecutive nucleotides in exon 11 that predicts a frame-shift of the mature mRNA with consequent premature termination of protein synthesis at codon 5 of the frame shift, or 1232 BRCA2:p.(Leu1227GlnfsTer5) using NP_000050.2. BRCA2 variants of this type are widely accepted to be pathogenic (Tayoun et al 2018, PMID: 30192042). This variant has been reviewed by the ENIGMA expert review panel: ENIGMA determine BRCA2:c.3680_3681delTG as consistent with an IARC Class 5 variant equivalent to ACMG classification of Pathogenic. This variant has been reported in the scientific literature in individuals with breast cancer (Wen et al., 2018 PMID:28993434), invasive lobular breast cancer (Petridis et al., 2019 PMID:31263054), and ovarian cancer (Cotrim et al., 2019 PMID:30606148). BRCA2: c.3680_3681delTG (rs80359395) is rare in population databases (gnomAD=0.01%) and is not on record in FLOSSIES. This variant is on record in ClinVar reported by multiple clinical laboratories as pathogenic in association with Breast-ovarian cancer, familial 2, Hereditary cancer-predisposing syndrome, and Hereditary breast and ovarian cancer syndrome (Variation ID:51504). This variant is listed in HGMD as ‘disease causing mutation’ in association with Ovarian cancer (Accession: CD011120). - |
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 | Sharing Clinical Reports Project (SCRP) | Mar 12, 2013 | - - |
Pathogenic, reviewed by expert panel | curation | Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) | Apr 22, 2016 | Variant allele predicted to encode a truncated non-functional protein. - |
Pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Feb 17, 2016 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Breast Cancer Information Core (BIC) (BRCA2) | May 29, 2002 | - - |
Pathogenic, criteria provided, single submitter | research | Laan Lab, Human Genetics Research Group, University of Tartu | May 01, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Genologica Medica | Jan 01, 2017 | - - |
Hereditary breast ovarian cancer syndrome Pathogenic:5
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 21, 2024 | This sequence change creates a premature translational stop signal (p.Leu1227Glnfs*5) 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 (rs80359395, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with breast and/or ovarian cancer (PMID: 11179017, 22762150, 24013928, 24728189, 24916970, 26845104, 27356891). This variant is also known as 3908_3909delTG. ClinVar contains an entry for this variant (Variation ID: 51504). 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 | Nov 05, 2020 | Variant summary: BRCA2 c.3680_3681delTG (p.Leu1227GlnfsX5) 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 249486 control chromosomes (gnomAD). c.3680_3681delTG has been reported in the literature in multiple individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (e.g. Peto_1999, Risch_2001, Miramar_2008, Lecarpentier_2012, Pal_2014). These data indicate that the variant is very likely to be associated with disease. Ten ClinVar submitters including an expert panel (ENIGMA) (evaluation 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 | Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego | - | This frameshifting variant in exon 11 of 28 introduces a premature stop codon and is therefore predicted to result in loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay (NMD). This variant has been previously reported as a heterozygous change in patients with breast and/or ovarian cancer (PMID: 11179017; 24013928; 25186627; 30159786). The c.3680_3681del variant is present in the heterozygous state in the gnomAD population database at a frequency of 0.00003% (1/31392) and thus is presumed to be rare. Based on the available evidence, the c.3680_3681del variant is classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Apr 24, 2019 | The p.Leu1227GlnfsX5 variant in BRCA2 has been reported in at least 8 individuals with BRCA2-associated cancers (Peto 1999, Risch 2001, Pal 2014, Breast Cancer Information Core (BIC) database). It has also been identified in 1/8710 African chromosomes by gnomAD (http://gnomad.broadinstitute.org); however, this frequency is low enough to be consistent with the frequency of hereditary breast and ovarian cancer (HBOC) in the general population. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 1227 and leads to a premature termination codon 5 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). In addition, this variant was classified as Pathogenic on April 22, 2016 by the ClinGen-approved ENIGMA expert panel (ClinVar SCV000282380.1). In summary, this variant meets our criteria to be classified as pathogenic for HBOC in an autosomal dominant manner based upon the predicted impact to the protein. ACMG/AMP criteria applied: PVS1, PS4_Moderate, PM2. - |
Pathogenic, no assertion criteria provided | research | Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto | Jan 31, 2014 | - - |
not provided Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Nov 23, 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; 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 3908_3909delTG; This variant is associated with the following publications: (PMID: 11179017, 26845104, 24013928, 27356891, 26287763, 22762150, 24916970, 23315985, 20167696, 24728189, 28127413, 28152038, 29907814, 29470806, 25186627, 28993434, 30606148, 30159786, 30720243, 31263054, 33654310, 31589614, 32427313, 30787465, 33087929) - |
Pathogenic, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The BRCA2 p.Leu1227Glnfs*5 variant was identified in 7 of 12390 proband chromosomes (frequency: 0.00056) from individuals or families with colorectal, breast or ovarian cancer (Dobbins 2016, Palmero 2018, Peixoto 2015, Shirts 2016, Song 2014). The variant was also identified in the following databases: dbSNP (ID: rs80359395) as "With Pathogenic allele ", ClinVar (classified as pathogenic by Invitae, Ambry Genetics, GeneDx and nine clinical laboratories), LOVD 3.0 (9x as pathogenic), UMD-LSDB (3x as causal ), BIC Database (8x with clinical importance), and in ARUP Laboratories (definitely pathogenic). The variant was not identified in Cosmic, Zhejiang University, the 1000 Genomes Project, the NHLBI GO Exome Sequencing Project, the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). The c.3680_3681del variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 1227 and leads to a premature stop codon at position 1231. 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 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. - |
Pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Mar 11, 2020 | This frameshift variant causes the premature termination of BRCA2 protein synthesis. In addition, it has been reported in individuals affected with breast and/or ovarian cancer and colorectal cancer in the published literature (PMIDs: 11179017 (2001), 24013928 (2014), 26287763 (2015), 27356891 (2016), 28993434 (2018), 29470806 (2018), 30159786 (2018), and 30606148 (2019)). Based on the available information, this variant is classified as pathogenic. - |
Hereditary cancer-predisposing syndrome Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 17, 2021 | The c.3680_3681delTG pathogenic mutation, located in coding exon 10 of the BRCA2 gene, results from a deletion of two nucleotides at positions 3680 to 3681, causing a translational frameshift with a predicted alternate stop codon (p.L1227Qfs*5). This alteration has been reported in numerous ancestrally diverse individuals with a personal and/or family history of breast and/or ovarian cancer (Peto J et al. J. Natl. Cancer Inst. 1999 Jun;91:943-9; Risch HA et al. Am. J. Hum. Genet. 2001 Mar;68:700-10; Miramar MD et al. Breast Cancer Res Treat. 2008 Nov;112:353-8; Zhang S et al. Gynecol. Oncol. 2011 May;121:353-7; Song H et al. Hum. Mol. Genet. 2014 Sep;23:4703-9; Pal T et al. Cancer. 2015 Dec;121:4173-80; Peixoto A et al. Clin Genet. 2015 Jul;88:41-8; Singh J et al. Breast Cancer Res Treat. 2018 Jul;170:189-196; Wen WX et al. J Med Genet. 2018 02;55:97-103; Cotrim DP et al. BMC Cancer. 2019 Jan;19:4; Petridis C et al. Cancer Epidemiol Biomarkers Prev. 2019 07;28:1162-1168; Santonocito C et al. Cancers (Basel). 2020 May;12:; Sandoval RL et al. PLoS One. 2021 Feb;16:e0247363). In addition, this alteration was reported in one individual with a personal history of early-onset familial colorectal cancer (Dobbins SE et al. Fam. Cancer 2016 Oct;15(4):593-9). Of note, this alteration is also designated as 3908delTG and 3908_3909delTG 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 | clinical testing | Color Diagnostics, LLC DBA Color Health | Mar 15, 2023 | This variant deletes 2 nucleotides in exon 11 of the BRCA2 gene, creating a frameshift and premature translation stop signal. This variant is also known as 3908delTG in the literature. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in multiple individuals and families affected with breast and/or ovarian cancer (PMID: 10359546, 11179017, 16826315, 18176857, 21324516, 22711857, 22762150, 24013928, 24916970, 26845104) and one individual each affected with endometrial and colorectal cancer (PMID: 24728189, 27356891). This variant has been identified in 1/31392 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 | curation | Sema4, Sema4 | Dec 07, 2021 | - - |
BRCA2-related disorder Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Oct 29, 2023 | The BRCA2 c.3680_3681delTG variant is predicted to result in a frameshift and premature protein termination (p.Leu1227Glnfs*5). This variant (also known as c.3908_3909delTG) has been reported as pathogenic in multiple individuals with a history of hereditary cancer syndromes (Song et al. 2014. PubMed ID: 24728189. Table S1; Risch et al. 2001. PubMed ID: 11179017; Pal et al. 2014. PubMed ID: 24013928; Dobbins et al. 2016. PubMed ID: 27356891;Bennett et al. 2021. PubMed ID: 33654310. Table S1). This variant is reported in 0.011% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/13-32912171-CTG-C). It is interpreted as pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/51504/). Frameshift variants in BRCA2 are expected to be pathogenic. This variant is interpreted as pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | DASA | Aug 10, 2022 | The c.3680_3681del;p.(Leu1227Glnfs*5) is a null frameshift variant (NMD) in the BRCA2 gene and predicts alteration of the nonsense-mediate decay - NMD is present in a relevant exon to the transcript - PVS1.This sequence change has been observed in affected individual(s) and ClinVar contains an entry for this variant(ClinVar ID: 51504; PMID: 24013928; 11179017; 24916970; 24728189; 22762150; 2684510) - PS4. The variant is present at low allele frequencies population databases (rs80359395 – gnomAD 0.00006573%; ABraOM no frequency - https://abraom.ib.usp.br/) -PM2_supporting. The variant co-segregated with disease in multiple affected family members (PMID: 24013928; 11179017; 24916970; 24728189; 22762150) -PP1. In summary, the currently available evidence indicates that the variant is pathogenic. - |
Familial cancer of breast Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Feb 27, 2024 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at