rs80358503
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000059.4(BRCA2):c.2376C>A(p.Tyr792*) 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
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0 ( 0 hom. )
Failed GnomAD Quality Control
Consequence
BRCA2
NM_000059.4 stop_gained
NM_000059.4 stop_gained
Scores
1
2
4
Clinical Significance
Conservation
PhyloP100: -0.255
Genes affected
BRCA2 (HGNC:1101): (BRCA2 DNA repair associated) Inherited mutations in BRCA1 and this gene, BRCA2, confer increased lifetime risk of developing breast or ovarian cancer. Both BRCA1 and BRCA2 are involved in maintenance of genome stability, specifically the homologous recombination pathway for double-strand DNA repair. The largest exon in both genes is exon 11, which harbors the most important and frequent mutations in breast cancer patients. The BRCA2 gene was found on chromosome 13q12.3 in human. The BRCA2 protein contains several copies of a 70 aa motif called the BRC motif, and these motifs mediate binding to the RAD51 recombinase which functions in DNA repair. BRCA2 is considered a tumor suppressor gene, as tumors with BRCA2 mutations generally exhibit loss of heterozygosity (LOH) of the wild-type allele. [provided by RefSeq, May 2020]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 13-32336731-C-A is Pathogenic according to our data. Variant chr13-32336731-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 51274.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr13-32336731-C-A is described in Lovd as [Pathogenic]. Variant chr13-32336731-C-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| BRCA2 | ENST00000380152.8 | c.2376C>A | p.Tyr792* | stop_gained | 11/27 | 5 | NM_000059.4 | ENSP00000369497.3 | ||
| BRCA2 | ENST00000530893.7 | c.2007C>A | p.Tyr669* | stop_gained | 11/27 | 1 | ENSP00000499438.2 | |||
| BRCA2 | ENST00000614259.2 | n.2376C>A | non_coding_transcript_exon_variant | 10/26 | 2 | ENSP00000506251.1 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
32
GnomAD3 exomes AF: 0.00000399 AC: 1AN: 250538Hom.: 0 AF XY: 0.00000738 AC XY: 1AN XY: 135584
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GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0AN: 1461650Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 727122
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Cov.:
32
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:13
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
Breast-ovarian cancer, familial, susceptibility to, 2 Pathogenic:6
| Pathogenic, no assertion criteria provided | clinical testing | Breast Cancer Information Core (BIC) (BRCA2) | May 22, 2003 | - - |
| 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, criteria provided, single submitter | clinical testing | Counsyl | Mar 25, 2016 | - - |
| 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 | Sharing Clinical Reports Project (SCRP) | Jan 18, 2007 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | BRCAlab, Lund University | Aug 26, 2022 | - - |
not provided Pathogenic:2
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Nov 21, 2023 | 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 individuals with a personal or family history consistent with pathogenic variants in this gene (PMID: 15876480, 28888541, 28111427, 29673794); 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 2604C>A; This variant is associated with the following publications: (PMID: 34413315, 15876480, 29446198, 30720243, 25525159, 31589614, 28127413, 18286383, 29673794, 28111427, 28888541, 29922827, 29625052) - |
| Pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Dec 05, 2020 | This nonsense variant causes the premature termination of BRCA2 protein synthesis. In addition, it has been reported in individuals affected with breast cancer in the published literature (PMID: 29446198 (2018), 18286383 (2008), 15876480 (2006)). Therefore, the variant is classified as pathogenic and this individual is at increased risk of developing BRCA2 related cancers. - |
Hereditary cancer-predisposing syndrome Pathogenic:2
| Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 16, 2024 | The p.Y792* pathogenic mutation (also known as c.2376C>A), located in coding exon 10 of the BRCA2 gene, results from a C to A substitution at nucleotide position 2376. This changes the amino acid from a tyrosine to a stop codon within coding exon 10. This mutation (designated as 2604C>A) has been identified in a Spanish high-risk breast cancer family (Salazar R et al. Cancer Lett, 2006 Feb;233:172-7). 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. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Nov 06, 2020 | 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. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with breast cancer (PMID: 15876480, 18286383). This variant has been identified in 1/250538 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 breast ovarian cancer syndrome Pathogenic:2
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Nov 13, 2024 | This sequence change creates a premature translational stop signal (p.Tyr792*) 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 (rs80358503, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with breast cancer (PMID: 15876480, 18286383). This variant is also known as 2604C>A. ClinVar contains an entry for this variant (Variation ID: 51274). For these reasons, this variant has been classified as Pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Nov 26, 2021 | Variant summary: BRCA2 c.2376C>A (p.Tyr792X) 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 allele was found at a frequency of 4e-06 in 250538 control chromosomes (gnomAD). c.2376C>A has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer Syndrome(e.g. Rebbeck_2018, Park_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. Seven submitters, including an expert panel (ENIGMA), have provided clinical-significance assessments for this variant in ClinVar after 2014, and all classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Familial cancer of breast Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Apr 20, 2023 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Uncertain
CADD
Uncertain
DANN
Uncertain
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Benign
N
Vest4
GERP RS
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at