rs80359322
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000059.4(BRCA2):c.2092delC(p.Leu698TyrfsTer32) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,162 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★★). 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
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
BRCA2 | ENST00000380152.8 | c.2092delC | p.Leu698TyrfsTer32 | frameshift_variant | Exon 11 of 27 | 5 | NM_000059.4 | ENSP00000369497.3 | ||
BRCA2 | ENST00000530893.7 | c.1723delC | p.Leu575TyrfsTer32 | frameshift_variant | Exon 11 of 27 | 1 | ENSP00000499438.2 | |||
BRCA2 | ENST00000614259.2 | n.2092delC | non_coding_transcript_exon_variant | Exon 10 of 26 | 2 | ENSP00000506251.1 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152162Hom.: 0 Cov.: 32
GnomAD4 exome Cov.: 33
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152162Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74334
ClinVar
Submissions by phenotype
Breast-ovarian cancer, familial, susceptibility to, 2 Pathogenic:6
- -
- -
This sequence change creates a premature translational stop signal (p.Leu698Tyrfs*32) 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 (ExAC no frequency). This premature translational stop signal has been observed in individual(s) with breast cancer (PMID: 15887246, 26681312). This variant is also known as 2320delC. For these reasons, this variant has been classified as Pathogenic. -
- -
- -
Variant allele predicted to encode a truncated non-functional protein. -
Hereditary breast ovarian cancer syndrome Pathogenic:3
This sequence change creates a premature translational stop signal (p.Leu698Tyrfs*32) 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 cancer (PMID: 15887246, 26681312). This variant is also known as 2320delC. ClinVar contains an entry for this variant (Variation ID: 37774). For these reasons, this variant has been classified as Pathogenic. -
The p.Leu698fs variant in BRCA2 has been reported in 2 individuals with breast cancer (Bonadona 2005 PMID: 15887246, Susswein 2015 PMID: 26681312). It was absent from large population studies. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 698 and leads to a premature termination codon 32 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 for hereditary breast and ovarian cancer (HBOC). In summary, this variant meets our criteria to be classified as pathogenic (http://pcpgm.partners.org/LMM) for HBOC in an autosomal dominant. ACMG/AMP criteria applied: PVS1, PM2_Supporting, PS4_Supporting. -
Variant summary: BRCA2 c.2092delC (p.Leu698TyrfsX32) 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 250696 control chromosomes. c.2092delC has been reported in the literature in individuals affected with Breast, Ovarian, and Prostate Cancer (example: Palmer_2020, De Talhouet_2020, Bonadona_2005, Susswein_2016, Wu_2018, Weber_2006) and was screened for patients with elevated risk for Breast and Ovarian cancer (example: Rebbeck_2018, Lecarpentier_2012). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Nine ClinVar submitters, including one expert panel and one consortia, have assessed the variant since 2014: all submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
not provided Pathogenic:2
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 personal or family history consistent with pathogenic variants in this gene (PMID: 15887246, 16550498); 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 2320del; 2320delC; This variant is associated with the following publications: (PMID: 16550498, 32073954, 15887246, 26681312, 32341426, 30787465, 26740259, 32427313, 31853058, 29446198, 22762150, 20104584) -
- -
Hereditary cancer-predisposing syndrome Pathogenic:2
The c.2092delC pathogenic mutation, located in coding exon 10 of the BRCA2 gene, results from a deletion of one nucleotide at nucleotide position 2092, causing a translational frameshift with a predicted alternate stop codon (p.L698Yfs*32). This mutation has been reported in multiple individuals with herediatry breast and/or ovarian cancer (Bonadona V et al. Genes Chromosomes Cancer 2005 Aug; 43(4):404-13; Susswein LR et al. Genet. Med. 2016 08;18(8):823-32; Rebbeck TR et al. Hum. Mutat. 2018 05;39(5):593-620). Of note, this mutation is also designated as 2320delC 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. -
- -
Familial cancer of breast Pathogenic:1
- -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at