rs80359004
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000059.4(BRCA2):c.7758G>A(p.Trp2586*) 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
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.7758G>A | p.Trp2586* | stop_gained | Exon 16 of 27 | 5 | NM_000059.4 | ENSP00000369497.3 | ||
| BRCA2 | ENST00000530893.7 | c.7389G>A | p.Trp2463* | stop_gained | Exon 16 of 27 | 1 | ENSP00000499438.2 | |||
| BRCA2 | ENST00000614259.2 | n.7758G>A | non_coding_transcript_exon_variant | Exon 15 of 26 | 2 | ENSP00000506251.1 |
Frequencies
GnomAD3 genomes
GnomAD4 exome Cov.: 31
GnomAD4 genome
ClinVar
Submissions by phenotype
Breast-ovarian cancer, familial, susceptibility to, 2 Pathogenic:6
The BRCA2 p.Trp2586* variant was identified in 18 of 62552 proband chromosomes (frequency: 0.0003) from individuals or families with breast and ovarian cancer (Callahan 2007, George 2013, Meindl 2002, Nahleh 2014, Perkowska 2003, Sinilnikova 2006, Weitzel 2005, Rebbeck 2018). The variant was also identified in dbSNP (ID: rs80359004) as "With Pathogenic allele", in ClinVar (classified 11x as Pathogenic by GeneDx, Ambry Genetics, SCRP and 8 other submitters), in Cosmic (identified once in squamous cell carcinoma from skin tissue and confirmed somatic status), in the LOVD 3.0 (8x pathogenic) and in the UMD-LSDB (1 record of causal biological significance) databases. The variant was not identified in the following control databases: the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). The p.Trp2586* variant leads to a premature stop codon at position 2586, 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. -
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Variant allele predicted to encode a truncated non-functional protein. -
_x000D_ Criteria applied: PVS1, PS4_MOD, PM2_SUP -
Hereditary breast ovarian cancer syndrome Pathogenic:5
This sequence change creates a premature translational stop signal (p.Trp2586*) 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, prostate and ovarian cancer (PMID: 2673801, 11802209, 16140926, 23035815, 23633455, 26681682). This variant is also known as c.7986G>A. ClinVar contains an entry for this variant (Variation ID: 38116). For these reasons, this variant has been classified as Pathogenic. -
Variant summary: The BRCA2 variant, c.7758G>A (p.Trp2586X) causes a nonsense mutation involving a conserved nucleotide resulting in a premature termination codon, a known mechanism for disease, as these types of variants are predicted to cause transcript degradation through nonsense mediated decay or produce a truncated protein. The variant of interest was not observed in controls (ExAC, 1000 Gs or ESP) and has been reported in multiple affected individuals via publications. In addition, multiple reputable databases/clinical laboratories cite the variant as "pathogenic." Therefore, taking all available lines of evidence into consideration, the variant of interest is classified as Pathogenic. -
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The p.Trp2586X variant in BRCA2 has been reported >5 individuals with BRCA2-asso ciated cancers (Meindl 2002, Callahan 2007, Conner 2014, Nahleh 2015, and Breast Cancer Information Core (BIC) database) and was absent from large population st udies. This nonsense variant leads to a premature termination codon at position 2586, which is predicted to lead to a truncated or absent protein. Heterozygous loss of function of the BRCA2 gene is an established disease mechanism in heredi tary breast and ovarian cancer (HBOC). In addition, this variant was classified as Pathogenic on September 8, 2016 by the ClinGen-approved ENIGMA expert panel ( ClinVar SCV000301200.2). In summary, this variant meets criteria to be classifie d as pathogenic for HBOC in an autosomal dominant manner based upon absence in c ontrols and the predicted impact to the protein. -
not provided Pathogenic:4
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The BRCA2 c.7758G>A; p.Trp2586Ter variant (rs80359004, ClinVar Variation ID: 38116) is reported in the literature in several individuals and families affected with breast and/or ovarian cancer (selected references: Abe 2022, Conner 2014, Meindl 2002, Nahleh 2014, Rebbeck 2018). This variant is absent from the Genome Aggregation Database (v2.1.1), 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 to be pathogenic. References: Abe A et al. Prevalence of Pathogenic Germline BRCA1/2 Variants and Their Association with Clinical Characteristics in Patients with Epithelial Ovarian Cancer in a Rural Area of Japan. Genes (Basel). 2022 Jun 18;13(6):1085. PMID: 35741847. Conner JR et al. Outcome of unexpected adnexal neoplasia discovered during risk reduction salpingo-oophorectomy in women with germ-line BRCA1 or BRCA2 mutations. Gynecol Oncol. 2014 Feb;132(2):280-6. PMID: 24333842. Meindl A et al. Comprehensive analysis of 989 patients with breast or ovarian cancer provides BRCA1 and BRCA2 mutation profiles and frequencies for the German population. Int J Cancer. 2002 Feb 1;97(4):472-80. PMID: 11802209. Nahleh Z et al. Clinical and pathological characteristics of Hispanic BRCA-associated breast cancers in the American-Mexican border city of El Paso, TX. Am J Cancer Res. 2014 Dec 15;5(1):466-71. PMID: 25628955. Rebbeck TR et al. Mutational spectrum in a worldwide study of 29,700 families with BRCA1 or BRCA2 mutations. Hum Mutat. 2018 May;39(5):593-620. PMID: 29446198. -
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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; Not observed in large population cohorts (Lek 2016); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Also known as BRCA2 7986G>A using alternate nomenclature; This variant is associated with the following publications: (PMID: 25628955, 11802209, 17761984, 24333842, 16140926, 25525159, 25371446, 21702907, 26564481, 16528604, 29446198, 31447099) -
Familial cancer of breast Pathogenic:2
Criteria applied: PVS1,PM5_STR,PM2_SUP -
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Hereditary cancer-predisposing syndrome Pathogenic:2
This variant changes 1 nucleotide in exon 16 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 reported in 5 individuals affected with breast and/or ovarian cancer, including 1 male individual and 1 individual affected with both breast and ovarian cancer (PMID: 24333842, 25628955, 33471991; Leiden Open Variation Database DB-ID BRCA2_00326233918338, 34377931). 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.W2586* pathogenic mutation (also known as c.7758G>A), located in coding exon 15 of the BRCA2 gene, results from a G to A substitution at nucleotide position 7758. This changes the amino acid from a tryptophan to a stop codon within coding exon 15. This mutation has been reported in multiple breast and/or ovarian cancer patients and families (Meindl A et al. Int J Cancer, 2002 Feb;97:472-80; Perkowska M et al. Hum. Mutat., 2003 May;21:553-4; Weitzel JN et al. Cancer Epidemiol Biomarkers Prev, 2005 Jul;14:1666-71; Jönsson G et al. Cancer Res, 2005 Sep;65:7612-21; Sinilnikova OM et al. Fam Cancer, 2006;5:15-20; Callahan MJ et al. J Clin Oncol, 2007 Sep;25:3985-90; Watson P et al. J Clin Oncol, 2009 Aug;27:3894-900; George J et al. Clin Cancer Res, 2013 Jul;19:3474-84; Conner JR et al. Gynecol Oncol, 2014 Feb;132:280-6; Nahleh Z et al. Am J Cancer Res, 2015 Dec;5:466-71; Eccles DM et al. Ann Oncol, 2016 Mar;27:467-73; Rebbeck TR et al. Hum Mutat, 2018 05;39:593-620; Dorling et al. N Engl J Med. 2021 02;384:428-439), as well as at least one prostate cancer patient (Willems-Jones A et al. BJU Int, 2012 Dec;110:E1181-6). Of note, this mutation is also designated as 7986G>A 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. -
Malignant tumor of urinary bladder Pathogenic:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at