rs80359444
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong
The NM_000059.4(BRCA2):c.4398_4402del(p.Leu1466PhefsTer2) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000748 in 1,604,428 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. E1465E) 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.4398_4402del | p.Leu1466PhefsTer2 | frameshift_variant | 11/27 | ENST00000380152.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BRCA2 | ENST00000380152.8 | c.4398_4402del | p.Leu1466PhefsTer2 | frameshift_variant | 11/27 | 5 | NM_000059.4 | A2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152172Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.00000405 AC: 1AN: 246640Hom.: 0 AF XY: 0.00000749 AC XY: 1AN XY: 133494
GnomAD4 exome AF: 0.00000689 AC: 10AN: 1452256Hom.: 0 AF XY: 0.00000694 AC XY: 5AN XY: 720520
GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152172Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1AN XY: 74334
ClinVar
Submissions by phenotype
Breast-ovarian cancer, familial, susceptibility to, 2 Pathogenic:7
Pathogenic, criteria provided, single submitter | clinical testing | Michigan Medical Genetics Laboratories, University of Michigan | Nov 03, 2014 | - - |
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 | Breast Cancer Information Core (BIC) (BRCA2) | May 29, 2002 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Nov 20, 2023 | This variant deletes 5 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. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with ovarian/breast cancer (PMID: 22711857, 24504028, 24728189, 26681312, 27406733) and prostate cancer (PMID: 17700570). This variant has been identified in 1/246640 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, 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 | Aug 30, 2016 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Sharing Clinical Reports Project (SCRP) | May 01, 2012 | - - |
not provided Pathogenic:4
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Jun 30, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Sep 15, 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; Observed in individuals with a personal or family history consistent with pathogenic variants in this gene (Agalliu et al., 2007; Cunningham et al., 2014; Song et al., 2014; Natarajan et al., 2016); 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 4625_4629delACATT and 1465_1467del; This variant is associated with the following publications: (PMID: 22144684, 17700570, 24504028, 24728189, 26681312, 27831900, 26295337, 27406733, 30267352, 10923033, 30720243, 30322717, 32719484, 32918181, 30787465, 33507482) - |
Pathogenic, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Sep 16, 2022 | PP5, PM2, PVS1 - |
Pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Oct 17, 2021 | - - |
Hereditary cancer-predisposing syndrome Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Apr 19, 2023 | This variant deletes 5 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 has been reported in individuals affected with ovarian/breast cancer (PMID: 22711857, 24504028, 24728189, 26681312, 27406733) and prostate cancer (PMID: 17700570). This variant has been identified in 1/246640 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 | Jun 20, 2022 | The c.4398_4402delACATT pathogenic mutation, located in coding exon 10 of the BRCA2 gene, results from a deletion of 5 nucleotides at nucleotide positions 4398 to 4402, causing a translational frameshift with a predicted alternate stop codon (p.L1466Ffs*2). This mutation (designated as 4625_4629delACATT) was reported in a Caucasian individual with prostate cancer diagnosed at age 51, who had a family history of prostate cancer in first-degree relatives, but no family history of breast or ovarian cancer (Agalliu I et al. Br. J. Cancer 2007 Sep;97(6):826-31). This mutation has also been reported in individuals with a personal history of breast, ovarian, and/or pancreatic cancer (Cunningham JM et al. Sci. Rep. 2014 Feb;4:4026; Natarajan P et al. Sci. Transl. Med. 2016 Nov;8(364):364ra151; Walker EJ et al. Fam. Cancer. 2019 Apr;18:241-251). This alteration was identified in a large, worldwide study of BRCA1/2 mutation positive families (Rebbeck TR et al. Hum. Mutat. 2018 05;39:593-620). 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 | Oct 22, 2021 | - - |
Hereditary breast ovarian cancer syndrome Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jul 02, 2019 | Variant summary: BRCA2 c.4398_4402delACATT (p.Leu1466PhefsX2) 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 249696 control chromosomes. c.4398_4402delACATT has been reported in the literature in multiple individuals affected with Breast and Ovarian Cancer (Alsop_2012, Song_2014, George_2016, Susswein_2016, Rebbeck_2018) and prostate cancer (Agalliu_2007). One publication, George_2016). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Nine ClinVar submissions including one 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 | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jul 15, 2021 | The p.Leu1466PhefsX2 variant in BRCA2 has been reported in at least 7 individuals with BRCA2-associated cancers (Agalliu 2007 PMID:17700570, Cunningham 2014 PMID:24504028, Susswein 2016 PMID:26681312, and Breast Cancer Information Core (BIC) database: https://research.nhgri.nih.gov/bic/). This variant has been identified in 0.003% (2/68012) European chromosomes by gnomAD (http://gnomad.broadinstitute.org, v3.1). 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 1466 and leads to a premature termination codon 2 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 individuals with hereditary breast and ovarian cancer (HBOC). Additionally, this variant was classified as pathogenic on April 22, 2016 by the ClinGen-approved ENIGMA expert panel (Variation ID 51640). 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. - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 08, 2024 | This sequence change creates a premature translational stop signal (p.Leu1466Phefs*2) 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 (rs755956766, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with breast, ovarian, and prostate cancer (PMID: 17700570, 24504028, 24728189, 26681312, 27406733, 27831900). This variant is also known as 4625_4629delACATT and 1465_1467del. ClinVar contains an entry for this variant (Variation ID: 51640). For these reasons, this variant has been classified as Pathogenic. - |
Malignant tumor of breast Pathogenic:1
Pathogenic, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The p.Leu1466PhefsX2 variant was not identified in the literature but was identified in dbSNP as a pathogenic allele (ID: rs80359444), in the Exome Aggregation Consortium (ExAC) database (released Jan 13, 2015) in 1 of 119188 chromosomes (frequency: 8.39E-06) (or 1 individual from a population of 32803 European (Non-Finnish) individuals and none from East Asian, African, Latino, South Asian, European (Finnish) or Other individuals. It was also identified in the Clinvitae database (4X), the ClinVar database (classified as a pathogenic variant by the Sharing Clinical Reports Project, derived from Myriad reports, Invitae, BIC, Ambry Genetics and GeneDX), the BIC database (3X with pathogenic clinical importance), and UMD (4X as a causal variant). The p.Leu1466PhefsX2 deletion variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 1466 and leads to a premature stop codon 2 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. - |
Familial cancer of breast Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Jan 10, 2024 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at