rs80356898
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong
The NM_007294.4(BRCA1):c.1687C>T(p.Gln563*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000093 in 1,613,306 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_007294.4 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00000658 AC: 1AN: 152074Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000280 AC: 7AN: 250426Hom.: 0 AF XY: 0.0000295 AC XY: 4AN XY: 135396
GnomAD4 exome AF: 0.00000958 AC: 14AN: 1461232Hom.: 0 Cov.: 34 AF XY: 0.0000124 AC XY: 9AN XY: 726908
GnomAD4 genome AF: 0.00000658 AC: 1AN: 152074Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74270
ClinVar
Submissions by phenotype
Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:20Other:1
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The c.1687C>T;p.(Gln563*) variant creates a premature translational stop signal in the BRCA1 gene. It is expected to result in an absent or disrupted protein product - PVS1. Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product (PMID: 12393792) - PS3_supporting. This sequence change has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 37426; PMID: 23199084; PMID: 24312913; PMID: 21989927; PMID: 25330149; PMID: 25948282; PMID: 26852130; PMID: 12393792) - PS4. The variant is present at low allele frequencies population databases (rs80356898 – gnomAD 0.0002795%; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2_supporting. In summary, the currently available evidence indicates that the variant is pathogenic. -
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_x000D_ Criteria applied: PVS1, PS4 -
PVS1, PS3, PS4_STR -
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ACMG classification criteria: PVS1 very strong, PVS1, PS3 supporting, PS4 strong, PS4, PM2 -
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Variant allele predicted to encode a truncated non-functional protein. -
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PVS1; PM5_PTC_Strong -
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ACMG criteria used to clasify this variant:PVS1, PS4_SUP, PM2_SUP -
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not provided Pathogenic:14
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BRCA1: PVS1, PM2, PS4:Moderate -
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The BRCA1 c.1687C>T; p.Gln563Ter variant (rs80356898), also known as 1806C>T, has been reported in multiple individuals with breast and/or ovarian cancer (Cunningham 2014, Maistro 2016, Shattuck-Eidens 1995, Wagner 1998). It is listed as pathogenic in ClinVar (Variation ID: 37426), and observed 6 times in the Genome Aggregation Database population database (6/245302 alleles). 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: Cunningham J et al. Clinical characteristics of ovarian cancer classified by BRCA1, BRCA2, and RAD51C status. Sci Rep. 2014; 4:4026. Maistro S et al. Germline mutations in BRCA1 and BRCA2 in epithelial ovarian cancer patients in Brazil. BMC Cancer. 2016; 16(1):934. Shattuck-Eidens D et al. A collaborative survey of 80 mutations in the BRCA1 breast and ovarian cancer susceptibility gene. Implications for presymptomatic testing and screening. JAMA. 1995; 273(7):535-41. Wagner T et al. BRCA1-related breast cancer in Austrian breast and ovarian cancer families: specific BRCA1 mutations and pathological characteristics. Int J Cancer. 1998; 77(3):354-60. -
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The BRCA1 c.1687C>T (p.Gln563*) variant causes the premature termination of BRCA1 protein synthesis. This variant has been reported in the published literature in numerous individuals with breast and/or ovarian cancer (PMIDs: 20104584 (2010), 26219728 (2016), 27425403 (2016), 27741520 (2016), 29335924 (2018), 33478551 (2021), 33670479 (2021), 38386807 (2024), 38785549 (2024)), as well as in individuals with pancreatic (PMIDs: 21989927 (2012), 32073954 (2020)), bladder (PMIDs: 32073954 (2020), 32073954 (2022)), and cervical cancer (PMID: 36451132 (2022)). Based on the available information, this variant is classified as pathogenic. -
The BRCA1 p.Gln563* variant was identified in 13 of 4212 proband chromosomes (frequency: 0.003) from individuals or families with breast or ovarian cancer and was present in 1 of 2600 control chromosomes (frequency: 0.0004) from healthy individuals (Alemar 2016, Cybulski 2015, Fernandes 2016, Jakimovska 2018, Kluska 2015, Maistro 2016, Meisel 2017). The variant was also identified in dbSNP (ID: rs80356898) as "With Pathogenic allele", ClinVar (classified as pathogenic by 23 submitters), LOVD 3.0 (49x as pathogenic), and UMD-LSDB (12x as causal). The variant was identified in control databases in 6 of 245302 chromosomes at a frequency of 0.00002 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the European population in 6 of 111186 chromosomes (freq: 0.00005), while it was not observed in the African, Other, Latino, Ashkenazi Jewish, East Asian, Finnish, or South Asian populations. The c.1687C>T variant leads to a premature stop codon at position 563, which is predicted to lead to a truncated or absent protein and loss of function. Loss of function variants of the BRCA1 gene are an established mechanism of disease in HBOC and is the type of variant expected to cause the disorder. In addition, one study demonstrated that this variant results in nonsense-mediated decay (Perrin-Vidoz 2002). In summary, based on the above information, this variant meets our laboratory’s criteria to be 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 individuals with a personal or family history consistent with pathogenic variants in this gene (Janavicius 2010, Ghiorzo 2012, Karami 2013, Meisel 2017); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Not observed at a significant frequency in large population cohorts (gnomAD); Also known as 1806C>T; This variant is associated with the following publications: (PMID: 24312913, 15024741, 15876480, 20373018, 21989927, 22776961, 24504028, 12566964, 11504767, 9663595, 23397983, 25948282, 26852130, 25525159, 18439106, 26843898, 27003155, 27376475, 27425403, 27194814, 7837387, 27914478, 27741520, 27836010, 28123851, 28127413, 28166811, 28281021, 28324225, 26681312, 28857155, 29339979, 29335924, 29907814, 29346284, 11251181, 29161300, 30103829, 30606148, 29446198, 30720243, 30322717, 31589614, 32341426, 33087929, 23199084) -
Hereditary breast ovarian cancer syndrome Pathogenic:6
Variant summary: The BRCA1 c.1687C>T (p.Gln563X) variant results in a premature termination codon, predicted to cause a truncated or absent BRCA1 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. This variant was found in 5/121138 control chromosomes at a frequency of 0.0000413, which does not exceed the estimated maximal expected allele frequency of a pathogenic BRCA1 variant (0.0010005). These occurrences need to be cautiously considered due to the cohort could harbor individuals with a BRCA1 phenotype. This variant has been reported in multiple HBOC patients and multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. -
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This sequence change creates a premature translational stop signal (p.Gln563*) in the BRCA1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in BRCA1 are known to be pathogenic (PMID: 20104584). This variant is present in population databases (rs80356898, gnomAD 0.005%). This premature translational stop signal has been observed in individual(s) with breast, ovarian, and pancreatic cancer (PMID: 21989927, 23199084, 24312913, 25330149, 25948282, 26852130). This variant is also known as 1806C>T. ClinVar contains an entry for this variant (Variation ID: 37426). For these reasons, this variant has been classified as Pathogenic. -
The p.Gln563X variant in BRCA1 (also referred to as 1806C>T) has been reported in >100 individuals with BRCA1-associated cancers (Shattuck-Eidens 1995, Wagner 1998, Pohlreich 2003, Foretova 2004, Salazar 2006, Krajc 2008, Janav 2010, Zuradelli 2010, Blay 2013, Cunningham 2014, Kluska 2015, Cini 2016, Breast Cancer Information Core (BIC) database). It was also identified in 5/66568 European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs80356898); however, this frequency is low enough to be consistent with the frequency of hereditary breast and ovarian cancer (HBOC) in the general population. This nonsense variant leads to a premature termination codon at position 563, which is predicted to lead to a truncated or absent protein. Heterozygous loss of function of the BRCA1 gene is an established disease mechanism in HBOC. Furthermore, this variant was classified as Pathogenic on April 22, 2016 by the ClinGen-approved ENIGMA expert panel (ClinVar SCV000282262.1). In summary, this variant meets criteria to be classified as pathogenic for HBOC in an autosomal dominant manner. PVS1, PM2, PS4. -
Hereditary cancer-predisposing syndrome Pathogenic:3
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The p.Q563* pathogenic mutation (also known as c.1687C>T), located in coding exon 9 of the BRCA1 gene, results from a C to T substitution at nucleotide position 1687. This changes the amino acid from a glutamine to a stop codon within coding exon 9. This mutation has been reported in numerous patients and families with hereditary breast and ovarian cancer (HBOC) syndrome (Shattuck-Eidens D et al. JAMA. 1995 Feb;273:535-41; Ghiorzo P et al. Fam. Cancer. 2012 Mar;11:41-7; Wong-Brown MW et al. Breast Cancer Res. Treat. 2015 Feb;150:71-80; Finch A et al. Clin. Genet. 2016 Mar;89:304-11; Fernandes GC et al. Oncotarget. 2016 Dec;7:80465-80481; Cotrim DP et al. BMC Cancer. 2019 Jan;19(1):4). This alteration has been described as a European founder mutation, having been detected in Austrian, Slovenian, Swedish and Polish populations (Janaviius R. EPMA J. 2010 Sep;1:397-412; Kluska A et al. BMC Med. Genomics. 2015 May;8:19). Of note, this alteration is also designated as 1806C>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 10 of the BRCA1 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 individuals affected with breast and/or ovarian cancer and in hereditary breast and ovarian cancer families (PMID: 20373018, 23479189, 24504028, 24728189, 25066507, 25330149, 26083025, 26219728, 26350514, 26852130, 27425403, 27741520, 28324225, 29335924, 30606148). This variant also has been detected in a breast cancer case-control meta-analysis in 12/60466 cases and 4/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA1_000161). This variant has been identified in 7/250426 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of BRCA1 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:2
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Familial cancer of breast Pathogenic:2
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This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PS1. -
Ovarian neoplasm Pathogenic:1
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Breast carcinoma;C0919267:Ovarian neoplasm Pathogenic:1
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Ovarian cancer Pathogenic:1
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BRCA1-related cancer predisposition Pathogenic:1
This variant changes 1 nucleotide in exon 10 of the BRCA1 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 individuals affected with breast and/or ovarian cancer and in hereditary breast and ovarian cancer families (PMID: 20373018, 23479189, 24504028, 24728189, 25066507, 25330149, 26083025, 26219728, 26350514, 26852130, 27425403, 27741520, 28324225, 29335924, 30606148, 36367610, 38386807, 38785549, 38922859). This variant also has been detected in a breast cancer case-control meta-analysis in 12/60466 cases and 4/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA1_000161). This variant has been identified in 7/250426 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of BRCA1 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. -
Familial cancer of breast;C2676676:Breast-ovarian cancer, familial, susceptibility to, 1;C3280442:Pancreatic cancer, susceptibility to, 4;C4554406:Fanconi anemia, complementation group S Pathogenic:1
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BRCA1-related disorder Pathogenic:1
The BRCA1 c.1687C>T variant is predicted to result in premature protein termination (p.Gln563*). This variant (also known as c.1806C>T in the literature) has been reported to be causative for breast, ovarian, and pancreatic cancer (Shattuck-Eidens et al. 1995. PubMed ID: 7837387; Susswein et al. 2016. PubMed ID: 26681312, Table S1; Ghiorzo et al. 2012. PubMed ID: 21989927; Schrader et al. 2012. PubMed ID: 22776961). This variant is reported in 0.0062% of alleles in individuals of European (Non-Finnish) descent in gnomAD and is interpreted as pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/37426/). Nonsense variants in BRCA1 are expected to be pathogenic. This variant is interpreted as pathogenic. -
Endometrial carcinoma Pathogenic:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at