Submissions for variant NM_000465.4(BARD1):c.1216C>T (p.Arg406Ter)

gnomAD frequency: 0.00003  dbSNP: rs377153250

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000217217	SCV000272972	pathogenic	Hereditary cancer-predisposing syndrome	2021-10-21	criteria provided, single submitter	clinical testing	The p.R406* pathogenic mutation (also known as c.1216C>T), located in coding exon 4 of the BARD1 gene, results from a C to T substitution at nucleotide position 1216. This changes the amino acid from an arginine to a stop codon within coding exon 4. This alteration has been seen in multiple breast cancer patients (Akcay IM et al. Int J Cancer, 2021 01;148:285-295; Weber-Lassalle N et al. Breast Cancer Res, 2019 04;21:55; Sun J et al. Clin Cancer Res, 2017 Oct;23:6113-6119). This alteration was also identified in a cohort of 3,579 African males diagnosed with prostate cancer who underwent multi-gene panel testing (Matejcic M et al. JCO Precis Oncol, 2020 Jan;4:32-43). 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	RCV000560121	SCV000632940	pathogenic	Familial cancer of breast	2023-12-18	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg406*) 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 (rs377153250, gnomAD 0.005%). This premature translational stop signal has been observed in individual(s) with breast cancer (PMID: 28724667). ClinVar contains an entry for this variant (Variation ID: 229677). Studies have shown that this premature translational stop signal is associated with altered splicing resulting in multiple RNA products (Invitae). For these reasons, this variant has been classified as Pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV000217217	SCV000682678	pathogenic	Hereditary cancer-predisposing syndrome	2022-09-09	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 cancer (PMID: 28724667; Fontaine et al., 2022, https://doi.org/10.21203/rs.3.rs-1584056/v1). This variant has been identified in 5/282366 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.
GeneDx	RCV000657592	SCV000779330	pathogenic	not provided	2023-06-16	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; Identified in individuals with a personal or family history of breast and other cancers (Sun et al., 2017; Weber-Lassalle et al., 2019; Huang et al., 2018; Akcay et al., 2020; Guo et al., 2020; Matejcic et al., 2020; Walsh et al., 2021); This variant is associated with the following publications: (PMID: 29625052, 32832836, 32658311, 31036035, 31887429, 31371347, 29922827, 33479248, 28724667)
CeGaT Center for Human Genetics Tuebingen	RCV000657592	SCV001153295	likely pathogenic	not provided	2023-08-01	criteria provided, single submitter	clinical testing	BARD1: PVS1
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000657592	SCV001905579	pathogenic	not provided	2021-09-15	criteria provided, single submitter	clinical testing
National Health Laboratory Service, Universitas Academic Hospital and University of the Free State	RCV002225514	SCV002505122	pathogenic	Hereditary breast ovarian cancer syndrome	2022-04-19	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002225514	SCV003928995	pathogenic	Hereditary breast ovarian cancer syndrome	2023-04-18	criteria provided, single submitter	clinical testing	Variant summary: BARD1 c.1216C>T (p.Arg406X) 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 allele was found at a frequency of 1.6e-05 in 250972 control chromosomes. c.1216C>T has been reported in the literature in individuals affected with Breast cancer (example, Sun_2017, Weber-Lassale_2019, Akcay_2021, Walsh_2021). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eight 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/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV000560121	SCV003936829	pathogenic	Familial cancer of breast	2023-07-06	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg406*) 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 identified in individuals with a personal or family history of breast and other cancers (Sun 2017, Weber-Lassalle 2019, Huang 2018, Akcay 2020, Guo 2020, Matejcic 2020) . This variant is present in population databases (rs377153250, gnomAD 0.005%). This premature translational stop signal has been observed in individual(s) with breast cancer (PMID: 28724667). ClinVar contains an entry for this variant (Variation ID: 229677). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. For these reasons, this variant has been classified as Pathogenic.
Myriad Genetics, Inc.	RCV000560121	SCV004044195	pathogenic	Familial cancer of breast	2023-05-22	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	RCV000560121	SCV004214939	pathogenic	Familial cancer of breast	2023-10-31	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000657592	SCV004238501	pathogenic	not provided	2019-03-28	criteria provided, single submitter	clinical testing
Medical Genetics Laboratory, Umraniye Training and Research Hospital, University of Health Sciences	RCV001554323	SCV001775489	pathogenic	Breast carcinoma	2021-08-09	no assertion criteria provided	clinical testing