ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.5154G>A (p.Trp1718Ter)

dbSNP: rs80357239
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Total submissions: 16
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) RCV000077604 SCV000300213 pathogenic Breast-ovarian cancer, familial, susceptibility to, 1 2016-09-08 reviewed by expert panel curation Variant allele predicted to encode a truncated non-functional protein.
GeneDx RCV000212195 SCV000210203 pathogenic not provided 2014-03-25 criteria provided, single submitter clinical testing This pathogenic variant is denoted BRCA1 c.5154G>A at the cDNA level and p.Trp1718Ter (W1718X) at the protein level. The substitution creates a nonsense variant, changing a Tryptophan to a premature stop codon (TGG>TGA). This variant is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. This variant, previously reported as 5273G>A using alternate nomenclature, has been reported in association with breast and/or ovarian cancer (Shattuck-Eidens 1997, Cao 2013). We therefore consider this variant to be pathogenic.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000077604 SCV000326185 pathogenic Breast-ovarian cancer, familial, susceptibility to, 1 2015-10-02 criteria provided, single submitter clinical testing
Genologica Medica RCV000077604 SCV000577936 pathogenic Breast-ovarian cancer, familial, susceptibility to, 1 2017-01-01 criteria provided, single submitter clinical testing
Color Diagnostics, LLC DBA Color Health RCV000580491 SCV000683265 pathogenic Hereditary cancer-predisposing syndrome 2020-01-15 criteria provided, single submitter clinical testing This variant is located in the BRCA1 protein. Splice site prediction tools suggest that this variant may not impact RNA splicing. This variant has not been identified 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000779910 SCV000916821 pathogenic Hereditary breast ovarian cancer syndrome 2018-11-29 criteria provided, single submitter clinical testing Variant summary: The BRCA1 c.5154G>A (p.Trp1718X) 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. The variant was absent in 245724 control chromosomes (gonmAD) and has been reported in the literature in multiple individuals affected with Hereditary Breast and Ovarian Cancer (Cao_2016, Li_2018, Jimenez _2013). These data indicate that the variant is very likely to be associated with disease. Four clinical diagnostic laboratories 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.
Invitae RCV000779910 SCV001582573 pathogenic Hereditary breast ovarian cancer syndrome 2023-07-17 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Trp1718*) 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 not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with personal and/or family history of hereditary breast and ovarian cancer (PMID: 9333265, 30720863). This variant is also known as 5273G>A. ClinVar contains an entry for this variant (Variation ID: 55434). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV000580491 SCV002641075 pathogenic Hereditary cancer-predisposing syndrome 2023-09-18 criteria provided, single submitter clinical testing The p.W1718* pathogenic mutation (also known as c.5154G>A), located in coding exon 17 of the BRCA1 gene, results from a G to A substitution at nucleotide position 5154. This changes the amino acid from a tryptophan to a stop codon within coding exon 17. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This alteration was detected in 1/798 individuals thought to be at elevated risk for a BRCA1 mutation based on personal and/or family history (Shattuck-Eidens D et al. JAMA, 1997 Oct;278:1242-50). It was also seen in two Chinese patients with personal and family histories of breast cancer (Cao W et al. Anat Rec (Hoboken), 2013 Feb;296:273-8). Of note, this alteration is also known as 5273G>A. 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.
Baylor Genetics RCV000077604 SCV004215171 pathogenic Breast-ovarian cancer, familial, susceptibility to, 1 2023-04-07 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000779910 SCV004848051 pathogenic Hereditary breast ovarian cancer syndrome 2017-05-12 criteria provided, single submitter clinical testing The c.5154G>A (p.Trp1718X) variant in BRCA1 has been identified in >5 individuals with BRCA1-associated cancers (Shattuck-Eidens 1997, Cao 2013, Cao 2016, Breast Cancer Information Core (BIC) database). In addition, another nucleotide change (c.5153G>A) that results in the same amino acid change (p.Trp1718X) has been identified in individuals with BRCA1-associated cancers (Dong 1998, Breast Cancer Information Core (BIC) database). The c.5154G>A variant was absent from large population studies. This nonsense variant leads to a premature termination codon at position 1718, 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 hereditary breast and ovarian cancer (HBOC). Furthermore, this variant was classified as Pathogenic on Sep 8, 2016 by the ClinGen-approved ENIGMA Expert Panel (ClinVar SCV000300213.2). In summary, this variant meets criteria to be classified as pathogenic for HBOC in an autosomal dominant manner.
Myriad Genetics, Inc. RCV000077604 SCV004930995 pathogenic Breast-ovarian cancer, familial, susceptibility to, 1 2024-01-03 criteria provided, single submitter clinical testing This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation.
Sharing Clinical Reports Project (SCRP) RCV000077604 SCV000109407 pathogenic Breast-ovarian cancer, familial, susceptibility to, 1 2013-05-10 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000077604 SCV000145361 pathogenic Breast-ovarian cancer, familial, susceptibility to, 1 2002-05-29 no assertion criteria provided clinical testing
Brotman Baty Institute, University of Washington RCV000077604 SCV001237785 not provided Breast-ovarian cancer, familial, susceptibility to, 1 no assertion provided in vitro
Department of Pathology and Laboratory Medicine, Sinai Health System RCV001358501 SCV001554253 pathogenic Malignant tumor of breast no assertion criteria provided clinical testing The BRCA1 p.Trp1718* variant was identified in 23 of 67354 proband chromosomes (frequency: 0.0003) from individuals or families with breast or ovarian cancer (Cao 2016, Kim 2015, Rebbeck 2018). The variant was also identified in dbSNP (ID: rs80357239) as "With Likely pathogenic , Pathogenic allele",ClinVar (classified as pathogenic by GeneDx, SCRP, Color and four other submitters), LOVD 3.0 (6x as pathogenic), and in UMD-LSDB (2x as causal). 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 c.5154G>A variant leads to a premature stop codon at position 1718 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 BRCA1 associated cancers 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.
BRCAlab, Lund University RCV000077604 SCV004243942 pathogenic Breast-ovarian cancer, familial, susceptibility to, 1 2020-03-02 no assertion criteria provided clinical testing

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