rs80358670
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000059.4(BRCA2):c.4325C>A(p.Ser1442*) 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.4325C>A | p.Ser1442* | stop_gained | Exon 11 of 27 | 5 | NM_000059.4 | ENSP00000369497.3 | ||
BRCA2 | ENST00000530893.7 | c.3956C>A | p.Ser1319* | stop_gained | Exon 11 of 27 | 1 | ENSP00000499438.2 | |||
BRCA2 | ENST00000614259.2 | n.4325C>A | non_coding_transcript_exon_variant | Exon 10 of 26 | 2 | ENSP00000506251.1 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD3 exomes AF: 0.00000415 AC: 1AN: 241106Hom.: 0 AF XY: 0.00000765 AC XY: 1AN XY: 130728
GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 6.94e-7 AC: 1AN: 1441002Hom.: 0 Cov.: 35 AF XY: 0.00000140 AC XY: 1AN XY: 713130
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
Breast-ovarian cancer, familial, susceptibility to, 2 Pathogenic:3
Variant allele predicted to encode a truncated non-functional protein. -
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Hereditary breast ovarian cancer syndrome Pathogenic:3
This sequence change creates a premature translational stop signal (p.Ser1442*) 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 (rs80358670, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with BRCA2-related conditions (PMID: 10923033). ClinVar contains an entry for this variant (Variation ID: 51633). For these reasons, this variant has been classified as Pathogenic. -
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Variant summary: BRCA2 c.4325C>A (p.Ser1442X) 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 (c.4415_4418delAGAA, p.Lys1472fsX6; c.4551_4554delAGAA, p.Lys1517fsX25; c.5682C>G, p.Tyr1894X). The variant allele was found at a frequency of 4.2e-06 in 237016 control chromosomes (gnomAD). This variant has been reported in the literature in individuals presumably affected with Hereditary Breast and Ovarian Cancer (Rebbeck_2018). 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. Six CliNVar submissions from clinical diagnostic laboratories (evaluation after 2014) cites the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
not provided Pathogenic:2
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; Not observed at significant frequency in large population cohorts (gnomAD); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Also known as 4553C>A; This variant is associated with the following publications: (PMID: 29922827, 28186126, 28152038, 29446198, 30720243, 30787465, 34308104, 31853058, 32377563, 32438681, 31869745) -
This nonsense variant causes the premature termination of BRCA2 protein synthesis. In addition, it has been reported in an individual with breast and/or ovarian cancer in the published literature (PMID: 32438681 (2020)). It has also been identified in a large cohort of BRCA1 and BRC2 mutation carriers (PMID 29446198 (2018)). Therefore, the variant is classified as pathogenic and this individual is at increased risk of developing BRCA2 related cancers. -
not specified Pathogenic:1
The BRCA2 c.4325C>A; p.Ser1442Ter variant (rs80358670), is reported in the literature in a validation study of pathogenic hereditary cancer variants (LaDuca 2017). This variant is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 51633), and is only observed on one allele in the Genome Aggregation Database. This variant induces an early termination codon and is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered to be pathogenic. References: LaDuca H et al. Exome sequencing covers >98% of mutations identified on targeted next generation sequencing panels. PLoS One. 2017 Feb 2;12(2):e0170843. -
BRCA2-related cancer predisposition Pathogenic:1
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 with a personal or family history of breast and/or ovarian cancer (PMID: 29446198, 32438681). This variant has been identified in 1/241106 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. -
Hereditary cancer-predisposing syndrome Pathogenic:1
The p.S1442* pathogenic mutation (also known as c.4325C>A), located in coding exon 10 of the BRCA2 gene, results from a C to A substitution at nucleotide position 4325. This changes the amino acid from a serine to a stop codon within coding exon 10. 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
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at