rs431825371
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000059.4(BRCA2):c.8837T>A(p.Leu2946*) 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.8837T>A | p.Leu2946* | stop_gained | Exon 22 of 27 | 5 | NM_000059.4 | ENSP00000369497.3 | ||
BRCA2 | ENST00000530893.7 | c.8468T>A | p.Leu2823* | stop_gained | Exon 22 of 27 | 1 | ENSP00000499438.2 | |||
BRCA2 | ENST00000614259.2 | n.*895T>A | non_coding_transcript_exon_variant | Exon 21 of 26 | 2 | ENSP00000506251.1 | ||||
BRCA2 | ENST00000614259 | n.*895T>A | 3_prime_UTR_variant | Exon 21 of 25 | 2 | ENSP00000506251.1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome Cov.: 31
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Breast-ovarian cancer, familial, susceptibility to, 2 Pathogenic:2
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Variant allele predicted to encode a truncated non-functional protein. -
Hereditary cancer-predisposing syndrome Pathogenic:2
This variant changes 1 nucleotide in exon 22 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 a male from affected with breast cancer and pancreatic cancer, with a family history breast and/or ovarian cancer (PMID: 29360161). 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. -
The p.L2946* pathogenic mutation (also known as c.8837T>A), located in coding exon 21 of the BRCA2 gene, results from a T to A substitution at nucleotide position 8837. This changes the amino acid from a leucine to a stop codon within coding exon 21. 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
This sequence change creates a premature translational stop signal (p.Leu2946*) 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 variant has not been reported in the literature in individuals affected with BRCA2-related conditions. ClinVar contains an entry for this variant (Variation ID: 96874). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -
Variant summary: BRCA2 c.8837T>A (p.Leu2946X) 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 250816 control chromosomes (gnomAD). The variant, c.8837T>A, has been reported in the literature in one individual affected with Hereditary Breast and Ovarian Cancer (Dudley_2018). The data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven ClinVar submissions including one expert panel (ENIGMA) (evaluation after 2014) cited the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
not specified Pathogenic:1
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BRCA2-related cancer predisposition Pathogenic:1
The c.8837T>A variant in the BRCA2 gene is located on exon 22 and introduces a premature translation termination codon (p.Leu2946*), resulting in an absent or disrupted protein product. The variant is reported in an individual with breast cancer and with the family history of breast and/or ovarian cancer (PMID: 29360161). Other protein termination codon variants in the same exon (p.Glu2947*, p.Gln2957*) have been reviewed as pathogenic by the expert panel (ClinVar ID: 91736, 38190). Loss-of-function variants in BRCA2 gene are known to be pathogenic (PMID: 8988179, 11897832, 29446198). The variant is reported in ClinVar as pathogenic (ID: 96874) and reviewed by the expert panel. The variant is absent in the general population database (gnomAD). Therefore, the c.8837T>A (p.Leu2946*) variant in the BRCA2 gene has been classified as pathogenic. -
not provided Pathogenic:1
Nonsense 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 an individual with pancreatic cancer and male breast cancer (PMID: 29360161); 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 9065T>A; This variant is associated with the following publications: (PMID: 30787465, 33277227, 28152038, 29360161) -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at