rs80359361
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000059.4(BRCA2):c.2899_2900del(p.Leu967ArgfsTer14) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,459,020 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. T966T) 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 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
BRCA2 | NM_000059.4 | c.2899_2900del | p.Leu967ArgfsTer14 | frameshift_variant | 11/27 | ENST00000380152.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BRCA2 | ENST00000380152.8 | c.2899_2900del | p.Leu967ArgfsTer14 | frameshift_variant | 11/27 | 5 | NM_000059.4 | A2 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome AF: 6.85e-7 AC: 1AN: 1459020Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 725726
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Breast-ovarian cancer, familial, susceptibility to, 2 Pathogenic:3
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, 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 | Breast Cancer Information Core (BIC) (BRCA2) | May 29, 2002 | - - |
Hereditary cancer-predisposing syndrome Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Jan 15, 2020 | This variant deletes 2 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 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. - |
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jul 21, 2020 | The c.2899_2900delCT pathogenic mutation, located in coding exon 10 of the BRCA2 gene, results from a deletion of two nucleotides at nucleotide positions 2899 to 2900, causing a translational frameshift with a predicted alternate stop codon (p.L967Rfs*14). This alteration has been reported in an individual with Fanconi anemia, who carried another pathogenic BRCA2 alteration (Myers K et al. Pediatr Blood Cancer 2012; 58:462-5). In one case control study, this alteration was detected in 1/2222 individuals with invasive epithelial ovarian cancer and 0/1528 matched controls. (Song H et al. Hum. Mol. Genet., 2014 Sep;23:4703-9) and in an individual diagnosed with breast cancer from Mexico (Millan Catalan O et al. Cancers (Basel), 2019 Aug;11:). This alteration was also 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. - |
Hereditary breast ovarian cancer syndrome Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Aug 30, 2019 | Variant summary: BRCA2 c.2899_2900delCT (p.Leu967ArgfsX14) 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. The variant was absent in 248436 control chromosomes (gnomAD). c.2899_2900delCT has been reported in the literature in multiple individuals affected with Breast and/or Ovarian Cancer (e.g. Caux-Moncoutier_2011, Cunningham_2014, Song_2014, Rebbeck_2018). The variant has also been reported in at least one individual with Fanconi anemia (Myers_2012, Degrolard-Courcet_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. Four submitters, including one expert panel (ENIGMA) have provided clinical-significance assessments for this variant in ClinVar after 2014, and all of them classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jul 12, 2023 | This sequence change creates a premature translational stop signal (p.Leu967Argfs*14) 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 and Fanconi anemia (PMID: 21120943, 21548014, 24504028). This variant is also known as 966_966del. ClinVar contains an entry for this variant (Variation ID: 125998). For these reasons, this variant has been classified as Pathogenic. - |
Familial cancer of breast Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Aug 10, 2022 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at