chr13-32379872-C-T
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000059.4(BRCA2):c.9076C>T(p.Gln3026*) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,190 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
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.9076C>T | p.Gln3026* | stop_gained | Exon 23 of 27 | 5 | NM_000059.4 | ENSP00000369497.3 | ||
| BRCA2 | ENST00000530893.7 | c.8707C>T | p.Gln2903* | stop_gained | Exon 23 of 27 | 1 | ENSP00000499438.2 | |||
| BRCA2 | ENST00000614259.2 | n.*1134C>T | non_coding_transcript_exon_variant | Exon 22 of 26 | 2 | ENSP00000506251.1 | ||||
| BRCA2 | ENST00000614259 | n.*1134C>T | 3_prime_UTR_variant | Exon 22 of 25 | 2 | ENSP00000506251.1 |
Frequencies
GnomAD3 genomes
GnomAD4 exome AF: 0.00000205 AC: 3AN: 1461190Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1AN XY: 726940
GnomAD4 genome
ClinVar
Submissions by phenotype
Breast-ovarian cancer, familial, susceptibility to, 2 Pathogenic:7
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Variant allele predicted to encode a truncated non-functional protein. -
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Hereditary breast ovarian cancer syndrome Pathogenic:5
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This sequence change creates a premature translational stop signal (p.Gln3026*) 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: 11595708, 19016756, 22632462, 25863477, 26187060, 27732944, 28008555, 28205045). ClinVar contains an entry for this variant (Variation ID: 38207). 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. -
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The p.Gln3026X variant in BRCA2 has been reported in >10 individuals with BRCA2- associated cancers (Ikeda 2001, Sekine 2001, Sugano 2008, Kang 2015, Arai 2018). It was also absent from large population studies. This nonsense variant leads t o a premature termination codon at position 3026, which is predicted to lead to a truncated or absent protein. Heterozygous loss of function of the BRCA2 gene i s an established disease mechanism in hereditary breast and ovarian cancer (HBOC ). In addition, this variant was classified as Pathogenic on Sep 8, 2016 by the ClinGen-approved ENIGMA expert panel (Variation ID 38207). In summary, the p.Gln 3026X variant meets criteria to be classified as pathogenic for HBOC in an autos omal dominant manner. ACMG/AMP criteria applied: PVS1, PS4_Moderate, PM2. -
Variant summary: BRCA2 c.9076C>T (p.Gln3026X) 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 (e.g. c.9093_9094delinsG/p.Thr3033fsX29, c.9097dupA/p.Thr3033fsX11). The variant was absent in 246292 control chromosomes (gnomAD). c.9076C>T has been reported in the literature in multiple individuals affected with Hereditary Breast and Ovarian Cancer (Malone_2006, Kang_2015, Palmero_2018). These data indicate that the variant is very likely to be associated with disease. Co-occurrence with another pathogenic variant has been reported (BRCA2 c.6237_6238delGT, p.Leu2080ArgfsX4) possibly in a patient with Fanconi Anemia (BRCA Share database). One study showed this variant did not significantly affect splicing (Acedo_2012). Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and all classified this variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
not provided Pathogenic:3
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; 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 9304C>T; This variant is associated with the following publications: (PMID: 22798144, 11149425, 33309985, 33057194, 36243179, 35982159, 28440963, 32980694, 32826389, 19016756, 25863477, 23893897, 26187060, 11595708, 28008555, 28205045, 27732944, 29439820, 30287823, 28111427, 29446198, 25525159, 31447099, 32710294, 30787465, 35741847, 31723001, 34645131, 29176636, 30350268, 22632462) -
The BRCA2 c.9076C>T, p.Gln3026Ter variant (rs80359159) has been reported in a family with breast and ovarian cancer (Sekine 2001). Minigene analysis indicates that the variant generates a transcript that leads to a premature termination codon through a frameshift or nonsense codon, or a transcript lacking 2 exons and approximately 101 amino acids (Acedo 2012). The variant is classified as pathogenic in ClinVar (Variation ID: 38207), but not observed in the general population databases (1000 Genomes Project, Exome Variant Server, Genome Aggregation Database). The variant introduces a premature termination codon, and is predicted to result in a truncated protein or an absent transcript. Based on the above information, the variant is classified as pathogenic. References: Acedo A et al. Comprehensive splicing functional analysis of DNA variants of the BRCA2 gene by hybrid minigenes. Breast Cancer Res. 2012; 14(3):R87. Sekine M et al. Mutational analysis of BRCA1 and BRCA2 and clinicopathologic analysis of ovarian cancer in 82 ovarian cancer families: two common founder mutations of BRCA1 in Japanese population. Clin Cancer Res. 2001; 7(10):3144-50. -
The BRCA2 c.9076C>T (p.Gln3026*) variant causes the premature termination of BRCA2 protein synthesis. This variant has been reported in the published literature in individuals with breast and/or ovarian cancer (PMIDs: 35741847 (2022), 34645131 (2022), 33471991 (2021), 32710294 (2021), 29907814 (2018), 29176636 (2018), 28205045 (2017), 25863477 (2015), 22798144 (2012), 19016756 (2008), 11595708 (2001)), including triple negative breast cancer (PMID: 30350268 (2018)) and male breast cancer (PMIDs: 30287823 (2018), 28008555 (2017)). Additionally, this variant has been reported in individuals with prostate cancer (PMID: 29439820 (2018)) and pancreatic cancer (PMID: 27732944 (2016)). Experimental studies show conflicting evidence of this variant's impact on splicing (PMIDs: 25525159 (2015), 22632462 (2012)). 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. -
Hereditary cancer-predisposing syndrome Pathogenic:2
The p.Q3026* pathogenic mutation (also known as c.9076C>T), located in coding exon 22 of the BRCA2 gene, results from a C to T substitution at nucleotide position 9076. This changes the amino acid from a glutamine to a stop codon within coding exon 22. This mutation has been identified in multiple hereditary breast and/or ovarian cancer families (Sekine M et al. Clin Cancer Res. 2001 Oct;7(10):3144-50; Arai M et al. J. Hum. Genet. 2018 Apr;63(4):447-457; Momozowa Y et al. Nat Commun 2018 10;9(1):4083). Of note, this mutation is also designated as 9304C>T in published literature. 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. -
This variant changes 1 nucleotide in exon 23 of the BRCA2 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. A minigene splicing assay has shown partial splicing defect (PMID: 22632462). This variant has been reported in at least a dozen individuals affected with breast or ovarian cancer (PMID: 11149425, 19016756, 22798144, 28008555, 30287823, 33471991; Leiden Open Variation Database DB-ID BRCA2_001520), in families suspected of being affected with hereditary breast and ovarian cancer (PMID: 11595708, 25863477) and in individuals affected with pancreatic or prostate cancer (PMID: 27732944, 31214711, 32980694). 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. -
Breast and/or ovarian cancer Pathogenic:1
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BRCA2-related disorder Pathogenic:1
The BRCA2 c.9076C>T variant is predicted to result in premature protein termination (p.Gln3026*). This variant was reported in multiple individuals with breast, ovarian cancer, or other cancers (see examples: Table 2, Sekine et al. 2001. PubMed ID: 11595708; Momozawa et al. 2018. PubMed ID: 30287823; Figure 1 and Table S1, Park. 2017. PubMed ID: 28111427; Table 1, Antonarakis. 2018. PubMed ID: 29439820). This variant has not been reported in a large population database, indicating this variant is rare. In ClinVar, this variant is interpreted as pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/38207/). Nonsense variants in BRCA2 are expected to be pathogenic. This variant is interpreted as pathogenic. -
Gastric cancer Pathogenic:1
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Malignant tumor of breast Pathogenic:1
The p.Gln3026X variant has been reported in 4 of 4712 proband chromosomes from individuals with breast or ovarian cancer (Sekine 2001, Sugano 2008, Kim 2012). This variant leads to a premature stop codon at position 3026, 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 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
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at