Submissions for variant NM_000465.4(BARD1):c.1921C>T (p.Arg641Ter)

gnomAD frequency: 0.00004  dbSNP: rs587781948

Total submissions: 17

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000130318	SCV000185168	pathogenic	Hereditary cancer-predisposing syndrome	2022-02-11	criteria provided, single submitter	clinical testing	The p.R641* pathogenic mutation (also known as c.1921C>T), located in coding exon 10 of the BARD1 gene, results from a C to T substitution at nucleotide position 1921. This changes the amino acid from an arginine to a stop codon within coding exon 10. This pathogenic mutation has been reported in several individuals diagnosed with breast cancer (De Brakeleer S et al. Clin. Genet. 2016 Mar;89:336-40; Feliubadaló L et al. Sci Rep, 2017 01;7:37984; Gass J et al. Clin Case Rep. 2017 Feb;5:104-107; Sun J et al. Clin. Cancer Res. 2017 Oct;23:6113-6119; Kaneyasu T et al. NPJ Breast Cancer, 2020 Jun;6:25; Rofes P et al. Genes (Basel), 2021 01;12:). It has also been reported in individuals with neuroblastoma and pancreatic cancer (Pugh TJ et al. Nat. Genet. 2013 Mar;45:279-84; Lasorsa VA et al. Oncotarget, 2016 Apr;7:21840-52; Hu C et al. Cancer Epidemiol Biomarkers Prev, 2016 Jan;25:207-11). 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000234673	SCV000284932	pathogenic	Familial cancer of breast	2024-01-31	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg641*) in the BARD1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in BARD1 are known to be pathogenic (PMID: 20077502, 21344236). This variant is present in population databases (rs587781948, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with neuroblastoma, pancreatic cancer, and breast cancer (PMID: 23334666, 26010302, 26483394, 28174632). ClinVar contains an entry for this variant (Variation ID: 141702). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000236005	SCV000293474	pathogenic	not provided	2024-01-18	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; Not observed at significant frequency in large population cohorts (gnomAD); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; This variant is associated with the following publications: (PMID: 26010302, 26483394, 32980694, 29922827, 26315354, 28174632, 28050010, 23334666, 29292755, 28055978, 28724667, 27009842, 32832836, 32566746, 33498765, 32427313, 32679805, 35892882, 36187937, 35353237, 36243179, 36493725, 34326862)
Color Diagnostics, LLC DBA Color Health	RCV000130318	SCV000682741	pathogenic	Hereditary cancer-predisposing syndrome	2022-12-13	criteria provided, single submitter	clinical testing	This variant changes 1 nucleotide in exon 10 of the BARD1 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 cancer, pancreatic cancer, or neuroblastoma (PMID: 23334666, 26010302, 26483394, 28174632, 28724667, 32566746, 33471991, 33498765). This variant has been identified in 5/282680 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of BARD1 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	RCV000781932	SCV000920362	pathogenic	Hereditary breast ovarian cancer syndrome	2019-10-28	criteria provided, single submitter	clinical testing	Variant summary: BARD1 c.1921C>T (p.Arg641X) 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. The variant allele was found at a frequency of 1.8e-05 in 282680 control chromosomes (gnomAD). c.1921C>T has been reported in the literature in multiple individuals affected with breast- and pancreatic cancer (e.g. DeBrakeleer_2016, Hu_2016, Feliubadalo_2017, Gas_2017). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, and all of them classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Cancer Genomics Group, Japanese Foundation For Cancer Research	RCV000781932	SCV001193493	pathogenic	Hereditary breast ovarian cancer syndrome	2019-05-01	criteria provided, single submitter	research
CeGaT Center for Human Genetics Tuebingen	RCV000236005	SCV001247080	pathogenic	not provided	2020-04-01	criteria provided, single submitter	clinical testing
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000236005	SCV001446723	pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000236005	SCV002046788	pathogenic	not provided	2021-03-28	criteria provided, single submitter	clinical testing	This nonsense variant causes the premature termination of BARD1 protein synthesis. In addition, it has been reported in multiple individuals and families affected with various cancers including breast cancer, pancreatic cancer, prostate cancer, and neuroblastoma in the published literature (PMID: 23334666 (2013), 26483394 (2015), 26010302 (2016), 28724667 (2017), 28174632 (2017), 28050010 (2017), 32566746 (2020), 32832836 (2020)). Based on the available information, this variant is classified as pathogenic.
Sema4, Sema4	RCV000130318	SCV002529559	pathogenic	Hereditary cancer-predisposing syndrome	2021-10-29	criteria provided, single submitter	curation
Myriad Genetics, Inc.	RCV000234673	SCV004044110	pathogenic	Familial cancer of breast	2023-05-24	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.
Baylor Genetics	RCV000234673	SCV004217207	pathogenic	Familial cancer of breast	2023-11-19	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000236005	SCV004238496	pathogenic	not provided	2023-07-10	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000236005	SCV005090525	pathogenic	not provided	2024-07-31	criteria provided, single submitter	clinical testing
Lab. Molecular Oncology, VUB, Free University of Brussels	RCV000678227	SCV000804246	pathogenic	Triple-Negative Breast Cancer Finding	2015-02-01	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001355804	SCV001550792	pathogenic	Malignant tumor of breast		no assertion criteria provided	clinical testing	The BARD1 p.Arg641* variant was identified in 3 of 712 proband chromosomes (frequency: 0.004) from individuals or families with breast cancer, pancreatic cancer and neuroblastoma (Pugh 2013, Hu 2016, De Brakeleer 2016). The variant was also identified in dbSNP (ID: rs587781948) as "With Pathogenic allele", ClinVar (3x pathogenic: Ambry genetics, Invitae, GeneDx), Clinvitae (3x pathogenic: Ambry genetics, Invitae, GeneDx), databases. The variant was not identified in COSMIC, MutDB, or the Zhejiang Colon Cancer Database. The variant was identified in control databases in 5 of 277022 chromosomes at a frequency of 0.00002 increasing the likelihood that this may be a low frequency benign variant in certain populations of origin (Genome Aggregation Consortium Feb 27, 2017). This mutation is expected to result in either nonsense mediated mRNA decay or, if translated, truncation of the protein product and absence of the last BRCA1 carboxy-terminal (BRCT) domain of the BARD1 protein. Loss of function variants of the BARD1 gene are an established mechanism of disease in breast 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.
Laboratory for Genotyping Development, RIKEN	RCV003162583	SCV002758549	pathogenic	Gastric cancer	2021-07-01	no assertion criteria provided	research