Submissions for variant NM_000465.4(BARD1):c.448C>T (p.Arg150Ter)

gnomAD frequency: 0.00001  dbSNP: rs730881411

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000159805	SCV000209833	pathogenic	not provided	2023-07-11	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); Observed in individuals with personal and/or family history of breast and/or ovarian cancer (Norquist et al., 2016; Lilyquist et al., 2017; Schoolmeester et al., 2017; Weber-Lassalle et al., 2019; Kaneyasu et al., 2020); This variant is associated with the following publications: (PMID: 26681312, 28709830, 26720728, 34426522, 32566746, 33084842, 32980694, 28888541, 31036035, 29922827)
Ambry Genetics	RCV000213814	SCV000273117	pathogenic	Hereditary cancer-predisposing syndrome	2022-03-02	criteria provided, single submitter	clinical testing	The p.R150* pathogenic mutation (also known as c.448C>T), located in coding exon 4 of the BARD1 gene, results from a C to T substitution at nucleotide position 448. This changes the amino acid from an arginine to a stop codon within coding exon 4. This mutation has previously been reported in the literature in two patients with breast cancer, one of whom also had a family history of breast and ovarian cancer in first and second degree relatives (Susswein LR et al. Genet. Med. 2016 Aug;18:823-32; Schoolmeester JK et al. Hum. Pathol. 2017 Dec;70:14-26). 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.
Invitae	RCV000471276	SCV000545633	pathogenic	Familial cancer of breast	2024-01-24	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg150*) 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 (rs730881411, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with breast cancer (PMID: 26681312, 28709830). ClinVar contains an entry for this variant (Variation ID: 182036). For these reasons, this variant has been classified as Pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV000213814	SCV000911007	pathogenic	Hereditary cancer-predisposing syndrome	2021-07-06	criteria provided, single submitter	clinical testing	This variant changes 1 nucleotide in exon 4 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, ovarian, and pancreatic cancer (PMID: 26681312, 26720728, 28709830, 29922827, 31036035, 32566746). This variant has been identified in 2/250728 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.
Cancer Genomics Group, Japanese Foundation For Cancer Research	RCV001030673	SCV001193501	pathogenic	Hereditary breast ovarian cancer syndrome	2019-05-01	criteria provided, single submitter	research
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001293502	SCV001482089	pathogenic	Malignant tumor of breast	2023-02-09	criteria provided, single submitter	clinical testing	Variant summary: BARD1 c.448C>T (p.Arg150X) 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 8e-06 in 250728 control chromosomes (gnomAD). c.448C>T has been reported in the literature in individuals affected with Breast Cancer (examples: Susswein_2016, Schoolmeester_2017, Weber-Lasalle_2019, and Ren_2021) and Ovarian Cancer (Norquist_2016). 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. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000159805	SCV002046427	pathogenic	not provided	2020-11-16	criteria provided, single submitter	clinical testing	This nonsense variant causes the premature termination of BARD1 protein synthesis. In addition, it has been reported in individuals affected with breast cancer in the published literature (PMID: 32566746 (2020), 31036035 (2019), 28709830 (2017), 26681312 (2015)). The frequency of this variant in the general population is consistent with pathogenicity. Therefore, the variant is classified as pathogenic.
Institute of Human Genetics, University of Leipzig Medical Center	RCV000471276	SCV003921057	pathogenic	Familial cancer of breast	2023-02-21	criteria provided, single submitter	clinical testing	_x000D_ Criteria applied: PVS1, PS4_MOD, PM2_SUP
Myriad Genetics, Inc.	RCV000471276	SCV004043400	pathogenic	Familial cancer of breast	2023-05-18	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	RCV000471276	SCV004214966	pathogenic	Familial cancer of breast	2023-10-16	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000159805	SCV004238506	pathogenic	not provided	2023-11-10	criteria provided, single submitter	clinical testing
Laboratory for Genotyping Development, RIKEN	RCV003162672	SCV002758038	pathogenic	Gastric cancer	2021-07-01	no assertion criteria provided	research