Submissions for variant NM_000465.4(BARD1):c.334C>T (p.Arg112Ter)

gnomAD frequency: 0.00001  dbSNP: rs758972589

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000164507	SCV000215158	pathogenic	Hereditary cancer-predisposing syndrome	2022-08-03	criteria provided, single submitter	clinical testing	The p.R112* pathogenic mutation (also known as c.334C>T), located in coding exon 3 of the BARD1 gene, results from a C to T substitution at nucleotide position 334. This changes the amino acid from an arginine to a stop codon within coding exon 3. This alteration was detected in a cohort of 8085 consecutive unselected Chinese breast cancer patients who underwent multi-gene panel testing (Sun L et al. Clin. Cancer Res. 2017 Oct;23(20):6113-6119), and has been reported in 1 of 124 patients with stage II-III triple negative breast cancer (González-Rivera M et al. Breast Cancer Res. Treat. 2016 Apr;156:507-515). This alteration has also been reported as a germline mutation in a cohort of patients with neuroblastoma tumors (Pugh TJ et al. Nat. Genet. 2013 Mar; 45(3):279-84. 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	RCV000233846	SCV000284955	pathogenic	Familial cancer of breast	2023-12-22	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg112*) 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 (rs758972589, gnomAD 0.007%). This premature translational stop signal has been observed in individual(s) with neuroblastoma (PMID: 23334666, 27083178). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 185139). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000413073	SCV000490424	pathogenic	not provided	2022-06-24	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 a significant frequency in large population cohorts (gnomAD); Observed in individuals with breast cancer, ovarian cancer, or neuroblastoma (Pugh 2013, Gonzalez-Rivera 2016, Sun 2017, Weber-Lassalle 2019, Suszynska 2020); This variant is associated with the following publications: (PMID: 23334666, 28985766, 27083178, 28055978, 28152038, 28724667, 29292755, 31036035, 32679805, 27535533, 32427313)
Color Diagnostics, LLC DBA Color Health	RCV000164507	SCV001357309	pathogenic	Hereditary cancer-predisposing syndrome	2020-01-15	criteria provided, single submitter	clinical testing	This variant changes 1 nucleotide in exon 3 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 identified in 2/251010 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	RCV002281980	SCV002570611	pathogenic	Malignant tumor of breast	2022-07-15	criteria provided, single submitter	clinical testing	Variant summary: BARD1 c.334C>T (p.Arg112X) 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 1.5e-05 in 259978 control chromosomes (gnomAD and Palmer_2020). c.334C>T has been reported in the literature in multiple individuals affected with breast cancer (e.g. Gonzalez-Rivera_ 2016, Tavera-Tapia_2017, Sun_2017, Weber-Lassalle_2019) and in individuals with neuroblastoma and ovarian cancer (e.g.Pugh_2013, Lilyquist_2017). These data indicate that the variant is likely to be associated with disease. Four clinical diagnostic laboratories and a professional group (CZECANCA consortium) have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000413073	SCV002774306	pathogenic	not provided	2021-08-26	criteria provided, single submitter	clinical testing	This nonsense variant causes the premature termination of BARD1 protein synthesis. It has been described in individuals with breast cancer and neuroblastoma in the published literature (PMIDs: 31036035 (2019), 30781715 (2019), 28724667 (2017), 27083178 (2016), and 23334666 (2013)). Based on the available information, this variant is classified as pathogenic.
Myriad Genetics, Inc.	RCV000233846	SCV004044112	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	RCV000233846	SCV004217287	pathogenic	Familial cancer of breast	2023-04-18	criteria provided, single submitter	clinical testing
CZECANCA consortium	RCV001270959	SCV001451763	pathogenic	Breast and/or ovarian cancer	2019-06-11	no assertion criteria provided	clinical testing