rs397507285
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000059.4(BRCA2):c.2426T>G(p.Leu809*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★★). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_000059.4 stop_gained
Scores
Clinical Significance
Conservation
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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.2426T>G | p.Leu809* | stop_gained | Exon 11 of 27 | 5 | NM_000059.4 | ENSP00000369497.3 | ||
BRCA2 | ENST00000530893.7 | c.2057T>G | p.Leu686* | stop_gained | Exon 11 of 27 | 1 | ENSP00000499438.2 | |||
BRCA2 | ENST00000614259.2 | n.2426T>G | non_coding_transcript_exon_variant | Exon 10 of 26 | 2 | ENSP00000506251.1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome Cov.: 33
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Breast-ovarian cancer, familial, susceptibility to, 2 Pathogenic:4
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Variant allele predicted to encode a truncated non-functional protein. -
This variant changes 1 nucleotide in exon 11 of the BRCA2 gene, creating a 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 breast and ovarian cancer or pancreatic cancer (PMID: 25186627, 26681312, 30051098). 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. -
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Hereditary breast ovarian cancer syndrome Pathogenic:3
This sequence change creates a premature translational stop signal (p.Leu809*) 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 and pancreatic cancer (PMID: 15728167, 26681312). ClinVar contains an entry for this variant (Variation ID: 37786). For these reasons, this variant has been classified as Pathogenic. -
Variant summary: BRCA2 c.2426T>G (p.Leu809X) 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 245558 control chromosomes. c.2426T>G has been reported in the literature in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (example: Tung_2014, Susswein_2015, Claus_2005). The following publications have been ascertained in the context of this evaluation (PMID: 15728167, 25186627, 26681312). ClinVar contains an entry for this variant (Variation ID: 37786). Based on the evidence outlined above, the variant was classified as pathogenic. -
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Hereditary cancer-predisposing syndrome Pathogenic:2
The p.L809* pathogenic mutation (also known as c.2426T>G), located in coding exon 10 of the BRCA2 gene, results from a T to G substitution at nucleotide position 2426. This changes the amino acid from a leucine to a stop codon within coding exon 10. This alteration has been reported in an individual with bilateral breast cancer, in an individual with early-onset breast cancer and ovarian cancer, and in an individual with pancreatic cancer in cohorts referred for clinical testing (Claus EB et al. JAMA. 2005 Feb;293:964-9; Tung N et al. Cancer 2015 Jan;121(1):25-33; Susswein LR et al. Genet. Med. 2016 Aug;18:823-32). 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. -
This variant changes 1 nucleotide in exon 11 of the BRCA2 gene, creating a 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 breast and ovarian cancer or pancreatic cancer (PMID: 25186627, 26681312, 30051098). 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. -
not provided Pathogenic:1
This variant is denoted BRCA2 c.2426T>G at the cDNA level and p.Leu809Ter (L809X) at the protein level. The substitution creates a nonsense variant, changing a Leucine to a premature stop codon (TTA>TGA). This variant is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. This variant, also known as 2654T>G using alternate nomenclature, has been reported in association with breast cancer (Claus 2005). We therefore consider this variant to be pathogenic. -
Familial cancer of breast Pathogenic:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at