chr13-32319259-C-T
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Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000059.4(BRCA2):c.250C>T(p.Gln84Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,482 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: 33)
Exomes 𝑓: 0.0000027 ( 0 hom. )
Consequence
BRCA2
NM_000059.4 stop_gained
NM_000059.4 stop_gained
Scores
2
3
2
Clinical Significance
Conservation
PhyloP100: 2.76
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 13-32319259-C-T is Pathogenic according to our data. Variant chr13-32319259-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 51298.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr13-32319259-C-T is described in Lovd as [Pathogenic]. Variant chr13-32319259-C-T is described in Lovd as [Pathogenic].
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
|---|---|---|---|---|---|---|---|
| BRCA2 | NM_000059.4 | c.250C>T | p.Gln84Ter | stop_gained | 3/27 | ENST00000380152.8 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| BRCA2 | ENST00000380152.8 | c.250C>T | p.Gln84Ter | stop_gained | 3/27 | 5 | NM_000059.4 | A2 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
33
GnomAD4 exome AF: 0.00000274 AC: 4AN: 1461482Hom.: 0 Cov.: 32 AF XY: 0.00000550 AC XY: 4AN XY: 727060
GnomAD4 exome
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32
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GnomAD4 genome
GnomAD4 genome
Cov.:
33
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:14Other:1
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
Breast-ovarian cancer, familial, susceptibility to, 2 Pathogenic:4Other:1
| Pathogenic, criteria provided, single submitter | clinical testing | Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge | Oct 02, 2015 | - - |
| not provided, no classification provided | clinical testing | Breast Cancer Information Core (BIC) (BRCA2) | - | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Sharing Clinical Reports Project (SCRP) | Jan 18, 2011 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | BRCAlab, Lund University | Mar 02, 2020 | - - |
| Pathogenic, reviewed by expert panel | curation | Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) | Apr 22, 2016 | Variant allele predicted to encode a truncated non-functional protein. - |
Hereditary breast ovarian cancer syndrome Pathogenic:4
| Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Apr 02, 2019 | The p.Gln84X variant in BRCA2 has been reported in >10 individuals with BRCA2-related cancers, as well as in one man with prostate cancer (Willems 2008, Turkovic 2010, Kwong 2012, Lang 2017, BIC database). It was absent from large population studies. This nonsense variant leads to a premature termination codon at position 84, which is predicted to lead to a truncated or absent protein. Loss of function of the BRCA2 gene is an established disease mechanism in autosomal dominant HBOC. In addition, this variant was classified as Pathogenic by the ClinGen-approved ENIGMA expert panel (Variation ID: 51298). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant HBOC. ACMG/AMP Criteria applied: PVS1, PM2, PS4_Moderate. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Dec 10, 2023 | This sequence change creates a premature translational stop signal (p.Gln84*) 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, ovarian and prostate cancer (PMID: 18445692, 20807450, 20858050, 21939546, 22970155). This variant is also known as 478C>T. ClinVar contains an entry for this variant (Variation ID: 51298). RNA analysis performed to evaluate the impact of this premature translational stop signal on mRNA splicing indicates it does not significantly alter splicing (Invitae). 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 | Aug 02, 2021 | Variant summary: BRCA2 c.250C>T (p.Gln84X) 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 251326 control chromosomes. c.250C>T has been reported in the literature in multiple individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (example, Rebbeck_2018). These data indicate that the variant is very likely to be associated with disease. One publication reports experimental evidence evaluating an impact on protein function, however, does not allow convincing conclusions about the variant effect. Multiple clinical diagnostic laboratories, an expert panel (ENIGMA) and a consortium (CIMBA) have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All sumbitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
| Pathogenic, no assertion criteria provided | research | Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto | Jan 31, 2014 | - - |
not provided Pathogenic:2
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jun 12, 2024 | 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: 20807450, 21939546, 22970155, 28294317); 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 478C>T; This variant is associated with the following publications: (PMID: 18445692, 26586665, 20858050, 26681312, 28294317, 29446198, 30702160, 20807450, 21939546, 22970155, 34399810, 30720863, 31825140, 31090900, 30787465, 20104584, 34887416, 37310942, 30145549, 31853058, 35216584) - |
| Pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Jan 19, 2021 | his nonsense variant causes the premature termination of BRCA2 protein synthesis. In addition, it has been reported in families affected with prostate cancer or breast/ovarian cancer in the published literature (PMID: 18445692 (2008), 21939546 (2011), 29446198 (2018), 30702160 (2019)). Analysis of this variant using software algorithms for the prediction of the effect of nucleotide changes on BRCA2 mRNA splicing yielded predictions that this variant may result in the gain of a cryptic splice site without affecting the natural splice sites . Based on the available information, this variant is classified as pathogenic. - |
Hereditary cancer-predisposing syndrome Pathogenic:2
| Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 13, 2024 | The p.Q84* pathogenic mutation (also known as c.250C>T), located in coding exon 2 of the BRCA2 gene, results from a C to T substitution at nucleotide position 250. This changes the amino acid from a glutamine to a stop codon within coding exon 2. This mutation has been reported in multiple individuals and families with Hereditary Breast and Ovarian Cancer (HBOC) syndrome (Willems AJ et al. Clin. Cancer Res., 2008 May;14:2953-61; Turkovic L et al. BMC Cancer, 2010;10:466; Coulet F et al. Genet Test Mol Biomarkers, 2010 Oct;14:677-90; Muller D et al. BMC Med. Genet., 2011 Sep;12:121; Kwong A et al. PLoS ONE, 2012 Sep;7:e43994; Susswein LR et al. Genet Med, 2016 08;18:823-32; Lang GT et al. Int J Cancer, 2017 07;141:129-142; Rebbeck TR et al. Hum Mutat, 2018 05;39:593-620; Nguyen-Dumont T et al. BMC Cancer, 2018 02;18:165; Deng M et al. Int J Cancer, 2019 09;145:1517-1528; Nones K et al. Ann Oncol, 2019 07;30:1071-1079). 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 | Mar 04, 2020 | This variant changes 1 nucleotide in exon 3 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 at high-risk for breast and/or ovarian cancer (PMID: 21939546, 22970155) and in an individual affected with prostate cancer from a family with multiple cases of breast cancer (PMID: 18445692). 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. - |
BRCA2-related disorder Pathogenic:1
| Pathogenic, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | May 06, 2024 | The BRCA2 c.250C>T variant is predicted to result in premature protein termination (p.Gln84*). This variant is also referred to as c.478C>T in literature. It has been reported in several individuals with breast or prostate cancer (see for example, Willems et al. 2008. PubMed ID: 18445692; Table S3, Lang et al. 2017. PubMed ID: 28294317; Table 2, Murali et al. 2021. PubMed ID: 34399810). It is interpreted as pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/51298/). This variant has not been reported in a large population database, indicating this variant is rare. Nonsense variants in BRCA2 are expected to be pathogenic. This variant is interpreted as pathogenic. - |
Familial cancer of breast Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Oct 30, 2021 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Benign
D
MutationTaster
Benign
A;A
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