Submissions for variant NM_000465.4(BARD1):c.1690C>T (p.Gln564Ter)

gnomAD frequency: 0.00003  dbSNP: rs587780021

Total submissions: 25

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000212135	SCV000149525	pathogenic	not provided	2022-04-16	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; Published functional studies demonstrate a damaging effect: significantly reduced homology-directed repair and may result in abnormal splicing (Ratajska 2015, Adamovich 2019); Case control studies suggest this variant is associated with breast cancer (Suszynska 2019); Observed in multiple individuals with personal and/or family history of breast, ovarian, colorectal, or endometrial cancer (Ratajska 2012, Blazer 2015, De Brakeleer 2015, Klonowska 2015, Ramus 2015, Maxwell 2016, Ring 2016, Weber-Lassalle 2019); This variant is associated with the following publications: (PMID: 25330149, 26075229, 26083025, 27443514, 31371347, 26681312, 31589614, 29922827, 28888541, 32726901, 21344236, 26010302, 25994375, 25980754, 26539620, 26738429, 26315354, 28030839, 27153395, 26329992, 30925164, 31036035, 28008555, 30675285, 31173646, 31142030, 29506128, 30947698, 31159747, 29625052, 26689913)
Ambry Genetics	RCV000115616	SCV000215789	pathogenic	Hereditary cancer-predisposing syndrome	2021-11-01	criteria provided, single submitter	clinical testing	The p.Q564* pathogenic mutation (also known as c.1690C>T), located in coding exon 8 of the BARD1 gene, results from a C to T substitution at nucleotide position 1690. This changes the amino acid from a glutamine to a stop codon within coding exon 8. This alteration has been reported in numerous patients diagnosed with breast and/or ovarian cancer (Ratajska M et al. Breast Cancer Res. Treat. 2012 Jan;131:89-97; Cybulski C et al. Clin. Genet. 2015 Oct;88:366-70; Klonowska K et al. Sci. Rep. 2015 May;5:10424; Ramus SJ et al. J Natl Cancer Inst. 2015 Nov;107:; Weber-Lassalle N et al. Breast Cancer Res. 2019 04;21:55; Shahi RB et al. BMC Cancer. 2019 Apr;19:313). Additionally, this alteration has been identified in a patient with triple-negative breast cancer (De Brakeleer S et al. Clin. Genet. 2016 Mar;89(3):336-40) and a male breast cancer patient (Pritzlaff M et al. Breast Cancer Res. Treat. 2017 Feb;161:575-586). 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	RCV000205536	SCV000260996	pathogenic	Familial cancer of breast	2024-01-26	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Gln564*) 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 (rs587780021, gnomAD 0.005%). This premature translational stop signal has been observed in individual(s) with breast and ovarian cancer (PMID: 21344236, 25994375, 26010302, 26315354, 26329992, 26681312, 27443514). ClinVar contains an entry for this variant (Variation ID: 127720). For these reasons, this variant has been classified as Pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV000115616	SCV000682724	pathogenic	Hereditary cancer-predisposing syndrome	2023-11-06	criteria provided, single submitter	clinical testing	This variant changes 1 nucleotide in exon 8 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 over 15 individuals affected with breast or ovarian cancer (PMID: 25994375, 26010302, 26315354, 26329992, 26681312, 28008555, 29625052, 30947698, 31036035, 32679805, 37239058, 37563628) and one individual affected with endometrial cancer (PMID: 27443514). In a large breast cancer case-control meta analysis, this variant has been observed in 17/60449 cases and 6/53455 controls (PMID: 33471991; Leiden Open Variation Database DB-ID BARD1_000187). This variant has been identified in 7/282686 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	RCV000588742	SCV000696755	pathogenic	Hereditary breast ovarian cancer syndrome	2019-12-10	criteria provided, single submitter	clinical testing	Variant summary: BARD1 c.1690C>T (p.Gln564X) 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. 5/5 computational tools predict no significant impact on normal splicing. However, Ratajska_2015 report that this variant may have an impact on splicing alteration. The variant allele was found at a frequency of 2.4e-05 in 252390 control chromosomes (gnomAD). c.1690C>T has been reported in the literature in multiple individuals affected with breast and/or ovarian cancer patients (e.g. Cybulski_2014, Weber-Lassalle_2019). These data indicate that the variant is very likely to be associated with disease. Nine other ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
GeneKor MSA	RCV000212135	SCV000821706	pathogenic	not provided	2020-01-01	criteria provided, single submitter	clinical testing	This variant results in the creation of a premature translational stop signal at codon 564 of the BARD1 protein (p.Gln564*). It is expected to result in absent or disrupted protein product. This variant has been described in the literature in patients with a strong family or personal history of breast and/or ovarian cancer (PMID: 21344236, PMID: 25994375, PMID: 26010302).The mutation database ClinVar contains an entry for this variant (Variation ID: 127720).
Mendelics	RCV000205536	SCV000837958	pathogenic	Familial cancer of breast	2018-07-02	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000212135	SCV000888798	pathogenic	not provided	2017-09-05	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000205536	SCV000893572	pathogenic	Familial cancer of breast	2018-10-31	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000212135	SCV001247082	pathogenic	not provided	2023-06-01	criteria provided, single submitter	clinical testing	BARD1: PVS1, PS3:Supporting, PS4:Supporting
Institute of Human Genetics, University of Leipzig Medical Center	RCV000205536	SCV001428829	uncertain significance	Familial cancer of breast	2019-01-01	criteria provided, single submitter	clinical testing
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000212135	SCV001447809	pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000212135	SCV002009151	pathogenic	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000115616	SCV002527045	pathogenic	Hereditary cancer-predisposing syndrome	2021-09-04	criteria provided, single submitter	curation
MGZ Medical Genetics Center	RCV000205536	SCV002579961	pathogenic	Familial cancer of breast	2022-07-20	criteria provided, single submitter	clinical testing
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000205536	SCV002762790	pathogenic	Familial cancer of breast	2022-12-09	criteria provided, single submitter	research	PVS1, PS3, PS4_STR
Myriad Genetics, Inc.	RCV000205536	SCV004044108	pathogenic	Familial cancer of breast	2023-05-23	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.
PreventionGenetics, part of Exact Sciences	RCV003415888	SCV004108471	pathogenic	BARD1-related condition	2023-07-12	criteria provided, single submitter	clinical testing	The BARD1 c.1690C>T variant is predicted to result in premature protein termination (p.Gln564*). This variant has been reported in many individuals with breast and/or ovarian cancer (Ratajska et al 2012. PubMed ID: 21344236; Yurgelun MB et al 2015. PubMed ID: 25980754; Klonowska K et al 2015. PubMed ID: 25994375; Ratajska M et al 2015. PubMed ID: 26329992; Lu C et al 2015. PubMed ID: 26689913; Maxwell KN et al 2016. PubMed ID: 27153395; Lilyquist J et al 2017. PubMed ID: 28888541; Lowery MA et al 2018. PubMed ID: 29506128; Huang KL et al 2018. PubMed ID: 29625052; Shahi RB et al 2019. PubMed ID: 30947698; Weber-Lassalle N et al 2019. PubMed ID: 31036035; Tsaousis GN et al 2019. PubMed ID: 31159747). This variant is reported in 0.0054% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/2-215610566-G-A) and is interpreted as pathogenic (15) and uncertain significance (1) in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/127720/). Nonsense variants in BARD1 are expected to be pathogenic. This variant is interpreted as pathogenic.
Baylor Genetics	RCV000205536	SCV004217284	pathogenic	Familial cancer of breast	2023-04-22	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000212135	SCV004238505	pathogenic	not provided	2021-01-21	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000212135	SCV004243118	pathogenic	not provided	2024-02-06	criteria provided, single submitter	clinical testing
Lab. Molecular Oncology, VUB, Free University of Brussels	RCV000678225	SCV000804244	pathogenic	Triple-Negative Breast Cancer Finding	2015-02-01	no assertion criteria provided	clinical testing
CZECANCA consortium	RCV001270956	SCV001451760	pathogenic	Breast and/or ovarian cancer	2019-06-11	no assertion criteria provided	clinical testing
BRCAlab, Lund University	RCV000205536	SCV002589054	pathogenic	Familial cancer of breast	2022-08-26	no assertion criteria provided	clinical testing
CZECANCA consortium	RCV003128144	SCV003804342	pathogenic	Endometrial carcinoma	2023-02-21	no assertion criteria provided	clinical testing