13-32380085-C-T
Variant summary
Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong
The NM_000059.4(BRCA2):c.9196C>T(p.Gln3066*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000041 in 1,461,776 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 (★★★). Synonymous variant affecting the same amino acid position (i.e. Q3066Q) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_000059.4 stop_gained
Scores
Clinical Significance
Conservation
Publications
- breast-ovarian cancer, familial, susceptibility to, 2Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), ClinGen
- Fanconi anemia complementation group D1Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, ClinGen, G2P
- pancreatic cancer, susceptibility to, 2Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
- sarcomaInheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
- hereditary breast ovarian cancer syndromeInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- Fanconi anemiaInheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
- medulloblastomaInheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
Genome browser will be placed here
ACMG classification
Our verdict: Pathogenic. The variant received 16 ACMG points.
Variant Effect in Transcripts
ACMG analysis was done for transcript: NM_000059.4. You can select a different transcript below to see updated ACMG assignments.
RefSeq Transcripts
| Selected | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| BRCA2 | NM_000059.4 | MANE Select | c.9196C>T | p.Gln3066* | stop_gained | Exon 24 of 27 | NP_000050.3 | ||
| BRCA2 | NM_001432077.1 | c.9196C>T | p.Gln3066* | stop_gained | Exon 24 of 27 | NP_001419006.1 | |||
| BRCA2 | NM_001406720.1 | c.9145C>T | p.Gln3049* | stop_gained | Exon 24 of 27 | NP_001393649.1 |
Ensembl Transcripts
| Selected | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| BRCA2 | ENST00000380152.8 | TSL:5 MANE Select | c.9196C>T | p.Gln3066* | stop_gained | Exon 24 of 27 | ENSP00000369497.3 | ||
| BRCA2 | ENST00000544455.6 | TSL:1 | c.9196C>T | p.Gln3066* | stop_gained | Exon 24 of 27 | ENSP00000439902.1 | ||
| BRCA2 | ENST00000530893.7 | TSL:1 | c.8827C>T | p.Gln2943* | stop_gained | Exon 24 of 27 | ENSP00000499438.2 |
Frequencies
GnomAD3 genomes
GnomAD4 exome AF: 0.00000410 AC: 6AN: 1461776Hom.: 0 Cov.: 32 AF XY: 0.00000550 AC XY: 4AN XY: 727188 show subpopulations
Age Distribution
GnomAD4 genome
ClinVar
Submissions by phenotype
Breast-ovarian cancer, familial, susceptibility to, 2 Pathogenic:6
Variant allele predicted to encode a truncated non-functional protein.
This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com.
PVS1; PM2_supporting; PM5_PTC_Strong
Hereditary breast ovarian cancer syndrome Pathogenic:6
The p.Gln3066X variant in BRCA2 has been reported >10 individuals with BRCA2-ass ociated cancers and in 2 individuals with Fanconi anemia have had a second BRCA2 pathogenic variant (Offit 2003, Alter 2007, Tai 2007, Fackenthal 2012, Cunningh am 2014, Song 2014, Couch 2015, Eccles 2016, Breast Cancer Information Core (BIC )). It was also absent from large population studies. This nonsense variant lead s to a premature termination codon at position 3066, which is predicted to lead to a truncated or absent protein. Heterozygous loss of function of the BRCA2 gen e is an established disease mechanism in hereditary breast and ovarian cancer (H BOC). In addition, this variant was classified as Pathogenic by the ClinGen-appr oved ENIGMA expert panel (ClinVar SCV000282469.1). In summary, this variant meet s criteria to be classified as pathogenic for HBOC in an autosomal dominant mann er. ACMG/Amp Criteria Applied: PVS1, PS4, PM2.
Variant summary: BRCA2 c.9196C>T (p.Gln3066X) 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 251286 control chromosomes. c.9196C>T has been widely reported in the literature in multiple individuals affected with Hereditary Breast And Ovarian Cancer Syndrome and subsequently cited by others (example Rebbeck_2018, a comprehensive collection of reported cases identified in the CIMBA database). These data indicate that the variant is very likely to be associated with disease. Eleven clinical diagnostic laboratories and one expert panel (ENIGMA) have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
This sequence change creates a premature translational stop signal (p.Gln3066*) 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 cancer, ovarian cancer, and Fanconi anemia (PMID: 14559878, 16825431, 24504028, 24728189, 26681682, 26845104). ClinVar contains an entry for this variant (Variation ID: 9347). For these reasons, this variant has been classified as Pathogenic.
not provided Pathogenic:3
The BRCA2 c.9196C>T; p.Gln3066Ter variant (rs80359180), also known as c.9424C>T, has been described in individuals with breast cancer, ovarian cancer, and Fanconi anemia (Alter 2007, Cunningham 2014, Fackenthal 2012, Offit 2003, Song 2014). It is reported as pathogenic by several laboratories in ClinVar (Variation ID: 9347) and is absent from general population databases (1000 Genomes Project, Exome Variant Server, and Genome Aggregation Database), indicating it is not a common polymorphism. 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 pathogenic. References: Alter B et al. Clinical and molecular features associated with biallelic mutations in FANCD1/BRCA2. J Med Genet. 2007 Jan;44(1):1-9. Cunningham J et al. Clinical characteristics of ovarian cancer classified by BRCA1, BRCA2, and RAD51C status. Sci Rep. 2014 Feb 7;4:4026. Fackenthal J et al. High prevalence of BRCA1 and BRCA2 mutations in unselected Nigerian breast cancer patients. Int J Cancer. 2012 Sep 1;131(5):1114-23. Offit K et al. Shared genetic susceptibility to breast cancer, brain tumors, and Fanconi anemia. J Natl Cancer Inst. 2003 Oct 15;95(20):1548-51. Song H et al. The contribution of deleterious germline mutations in BRCA1, BRCA2 and the mismatch repair genes to ovarian cancer in the population. Hum Mol Genet. 2014 Sep 1;23(17):4703-9.
This variant causes the premature termination of BRCA2 protein synthesis. In the published literature, this variant has been reported in individuals with breast/ovarian cancer, and male breast cancer (PMIDs: 30322717 (2018), 29433453 (2018), 25452441 (2015), 24504028 (2014), 18042939 (2007)). Additionally, this variant has been reported in compound heterozygous individuals with Fanconi anemia (PMIDs: 16825431 (2007), 14559878 (2003)). 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.
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 the heterozygous state in multiple individuals with a personal or family history consistent with pathogenic variants in this gene (Tai et al., 2007; Fackenthal et al., 2012; Cunningham et al., 2014; Couch et al., 2015; Eccles et al., 2016); Not observed at significant frequency in large population cohorts (Lek et al., 2016); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Also known as 9424C>T; This variant is associated with the following publications: (PMID: 28152038, 25452441, 24504028, 21702907, 24301060, 16825431, 22034289, 18042939, 15689453, 24259538, 26064523, 14559878, 26724258, 26708042, 26681682, 29433453, 29446198, 30322717, 30787465, 25525159, 32885271)
Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:2
Hereditary cancer-predisposing syndrome Pathogenic:2
This variant changes 1 nucleotide in exon 24 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 detected in at least six individuals affected with breast and/or ovarian cancer (PMID: 17592676, 22034289, 24504028, 24728189, 25452441, 26681682, 26845104) and an individual affected with prostate cancer (PMID: 26724258). This variant also has been detected in compound heterozygosity in an individual affected with Fanconi anemia (PMID: 14559878). 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.Q3066* pathogenic mutation (also known as c.9196C>T), located in coding exon 23 of the BRCA2 gene, results from a C to T substitution at nucleotide position 9196. This changes the amino acid from a glutamine to a stop codon within coding exon 23. This pathogenic mutation has been described in individuals with male breast cancer, ovarian cancer, triple negative breast cancer, early onset breast cancer and prostate cancer (Tai YC et al. J. Natl. Cancer Inst. 2007 Dec;99:1811-4; Cunningham JM et al. Sci. Rep. 2014 Feb;4:4026; Couch FJ et al. J. Clin. Oncol. 2015 Feb;33(4):304-11; Eccles DM et al. Ann. Oncol. 2016 Mar;27(3):467-73; Cheng HH et al. Eur. Urol. 2016 Jun;69(6):992-5). In two unrelated children with Fanconi anemia (FA), this mutation was reported in conjunction with a second pathogenic BRCA2 mutation (Offit K et al. J. Natl. Cancer Inst. 2003 Oct;95:1548-51; Alter BP et al. J. Med. Genet. 2007 Jan;44:1-9). Of note, this alteration is also designated as 9424C>T in published literature. 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. However, because this variant is identified in one or more patients with Fanconi Anemia it may be hypomorphic and thus, carriers of this variant and their families may present with reduced risks, and not with the typical clinical characteristics of a high-risk pathogenic BRCA2 alteration. As risk estimates are unknown at this time, clinical correlation is advised.
Fanconi anemia complementation group D1 Pathogenic:1
BRCA2-related cancer predisposition Pathogenic:1
This variant changes 1 nucleotide in exon 24 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 detected in at least six individuals affected with breast and/or ovarian cancer (PMID: 17592676, 22034289, 24504028, 24728189, 25452441, 26681682, 26845104) and an individual affected with prostate cancer (PMID: 26724258). This variant also has been detected in compound heterozygosity in an individual affected with Fanconi anemia (PMID: 14559878). 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.
Malignant tumor of breast Pathogenic:1
The BRCA2 p.Gln3066X variant was identified in an African American individual with Fanconi anemia, as a compound heterozygote (BRCA2 Q3066X/E1308X) (Offit 2003), and in a serous (epithelial ovarian) cancer (Song 2014). The variant was also identified in dbSNP (ID: rs80359180) as With Pathogenic, Uncertain significance allele, ClinVar (classified as pathogenic by Ambry Genetics, OMIM, SCRP, BIC), Clinvitae (classified as pathogenic by ClinVar), BIC Database (5X with clinical importance), ARUP Laboratories (as definitely pathogenic), databases. The variant was not identified in Genesight-COGR, LOVD 3.0, UMD-LSDB, Zhejiang Colon Cancer Database, databases. The variant was not identified in the 1000 Genomes Project, the NHLBI GO Exome Sequencing Project or the Exome Aggregation Consortium (August 8th 2016) control databases. The p.Gln3066X variant leads to a premature stop codon at position 3066, which is predicted to lead to a truncated or absent protein and loss of function. Loss of function variants of the BRCA2 gene are an established mechanism of disease in hereditary breast and ovarian cancer and is the type of variant expected to cause the disorder. In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic.
Familial cancer of breast Pathogenic:1
Cancer or benign tumor Pathogenic:1
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at