rs80358721
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000059.4(BRCA2):c.4965C>A(p.Tyr1655Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000138 in 1,449,370 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: 0.0000014 ( 0 hom. )
Consequence
BRCA2
NM_000059.4 stop_gained
NM_000059.4 stop_gained
Scores
2
1
4
Clinical Significance
Conservation
PhyloP100: -0.524
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 13-32339320-C-A is Pathogenic according to our data. Variant chr13-32339320-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 51750.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr13-32339320-C-A is described in Lovd as [Pathogenic]. Variant chr13-32339320-C-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| BRCA2 | NM_000059.4 | c.4965C>A | p.Tyr1655Ter | stop_gained | 11/27 | ENST00000380152.8 | NP_000050.3 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| BRCA2 | ENST00000380152.8 | c.4965C>A | p.Tyr1655Ter | stop_gained | 11/27 | 5 | NM_000059.4 | ENSP00000369497 | A2 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
33
GnomAD4 exome AF: 0.00000138 AC: 2AN: 1449370Hom.: 0 Cov.: 46 AF XY: 0.00000139 AC XY: 1AN XY: 720172
GnomAD4 exome
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2
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1449370
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46
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1
AN XY:
720172
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GnomAD4 genome
GnomAD4 genome
Cov.:
33
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:19
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
Breast-ovarian cancer, familial, susceptibility to, 2 Pathogenic:7
| Pathogenic, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Breast Cancer Information Core (BIC) (BRCA2) | Jul 11, 2002 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Sharing Clinical Reports Project (SCRP) | Oct 12, 2012 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | Oct 08, 2014 | - - |
| 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 | BRCAlab, Lund University | Aug 26, 2022 | - - |
| 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 Pathogenic:4
| Pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | May 22, 2023 | This variant causes the premature termination of BRCA2 protein synthesis. In the published literature, this variant has been reported in individuals and families with breast and/or ovarian cancer (PMIDs: 33471991 (2021), 29446198 (2018), 30287823 (2018), 25136594 (2014)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Based on the available information, this variant is classified as pathogenic. - |
| Pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Dec 21, 2022 | 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 BRCA2-related cancers (Sakai 2009, Caux-Moncoutier 2011); Published functional studies support a damaging effect: sensitivity to cisplatin (Sakai 2009); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Not observed in large population cohorts (gnomAD); Also known as 5193C>A; This variant is associated with the following publications: (PMID: 25136594, 19654294, 21120943, 25525159, 29446198, 21205087, 30287823, 32377563, 33087929) - |
| Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Oct 01, 2023 | BRCA2: PVS1, PM2 - |
Hereditary breast ovarian cancer syndrome Pathogenic:4
| Pathogenic, no assertion criteria provided | research | Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto | Jan 31, 2014 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 27, 2024 | This sequence change creates a premature translational stop signal (p.Tyr1655*) 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 and/or ovarian cancer (PMID: 17688236, 20858050, 21120943, 21709188, 23569316, 24728189, 25136594, 26681312, 29446198, 29487695). ClinVar contains an entry for this variant (Variation ID: 51750). For these reasons, this variant has been classified as Pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Mendelics | Jul 02, 2018 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Oct 14, 2019 | The p.Tyr1655X (c.4965C>A) variant in BRCA2 has been reported in at least 3 individuals with breast cancer (Caux-Moncoutier 2010, BIC database). It was absent from large population studies. This nonsense variant leads to a premature termination codon at position 1655, 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 hereditary breast and ovarian cancer syndrome (HBOC). Additionally, this variant was classified as Pathogenic on Sept 8 2016 by the ClinGen-approved ENIGMA expert panel (Variation ID: 51750). Another variant at this position, c.4965C>G, resulting in the same amino acid change, has been identified in individuals with HBOC and is classified as pathogenic by this laboratory. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant HBOC. ACMG/AMP Criteria applied: PVS1, PM2, PS4_Supporting, PS1. - |
Hereditary cancer-predisposing syndrome Pathogenic:2
| Pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Jan 15, 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. 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. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 27, 2023 | The p.Y1655* pathogenic mutation (also known as c.4965C>A), located in coding exon 10 of the BRCA2 gene, results from a C to A substitution at nucleotide position 4965. This changes the amino acid from a tyrosine to a stop codon within coding exon 10. In one study, this variant was observed in 1/1525 unrelated patients who had BRCA1/2 genetic testing due to a personal and/or family history suspicious for Hereditary Breast and/or Ovarian Cancer (Caux-Moncoutier V et al. Hum. Mutat., 2011 Mar;32:325-34). This alteration was also identified in a large, worldwide study of BRCA1/2 mutation positive families (Rebbeck TR et al. Hum. Mutat., 2018 05;39:593-620) and has been reported with a carrier frequency of 0.00014 in 7051 unselected breast cancer patients and 0.00000 in 11241 female controls of Japanese ancestry (Momozawa Y et al. Nat Commun, 2018 10;9:4083). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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. - |
FLG-related disorder Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego | - | This frameshifting variant in exon 11 of 28 is predicted to result in loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. This variant has been previously reported as a heterozygous change in patients with BRCA2-related cancers (PMID: 17688236, 19654294, 20858050, 21709188, 23569316, 24728189, 25136594, 26681312, 28973083, 29371908). Loss-of-function variation in BRCA2 is an established mechanism of disease (ClinVar; HGMD Database). The c.4965C>A (p.Tyr1655Ter) variant is absent from the gnomAD population database and thus is presumed to be rare. Based on the available evidence, the c.4965C>A (p.Tyr1655Ter) variant is classified as Pathogenic. - |
Familial cancer of breast Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Sep 02, 2023 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Benign
N
MutationTaster
Benign
A;A
Vest4
GERP RS
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at