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

dbSNP: rs80357239

Total submissions: 17

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	2024-04-09	criteria provided, single submitter	clinical testing	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 5273G>A; This variant is associated with the following publications: (PMID: 29884136, 30702160, 31589614, 29446198, 25525159, 30078507, 34254208, 9333265, 30209399, 30720863, 23175448)
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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000779910	SCV001582573	pathogenic	Hereditary breast ovarian cancer syndrome	2023-07-17	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 55434). This variant is also known as 5273G>A. 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 not present in population databases (gnomAD no frequency). 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).
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.
Molecular Diagnostics Laboratory, Catalan Institute of Oncology	RCV000580491	SCV005870899	pathogenic	Hereditary cancer-predisposing syndrome	2024-08-28	criteria provided, single submitter	clinical testing	PVS1, PS3, PM5_PTC_Strong, PM2_Supporting c.5154G>A, located in exon 18 (19 according BIC nomenclature) of the BRCA1 gene, is a nonsense variant expected to result in loss of function by premature protein truncation and nonsense-mediated mRNA decay, p.(Trp1718*)(PVS1, PM5_PTC_Strong). No effect is predicted on splicing by SpliceAI. It is not present in the population database gnomAD v2.1.1, non cancer dataset (PM2_Supporting). Reported by one calibrated study to affect protein function similar to pathogenic control variants (PMID:30209399) (PS3). To our knowledge, no relevant clinical data has been reported for this variant. In addition, the variant was also identified in the following databases: BRCA Exchange (pathogenic: “Variant allele predicted to encode a truncated non-functional protein”), ClinVar (14x pathogenic) and LOVD (7x pathogenic). Reported by one calibrated study to affect protein function similar to pathogenic control variants (PMID:30209399) (PS3). Based on currently available information, c.5154G>A is classified as a pathogenic variant according to ClinGen-BRCA1 Guidelines version v1.0.0.
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