Submissions for variant NM_000465.4(BARD1):c.33G>T (p.Gln11His)

gnomAD frequency: 0.00176  dbSNP: rs143914387

Total submissions: 24

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000587822	SCV000149542	likely benign	not provided	2020-09-26	criteria provided, single submitter	clinical testing	In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 27978560, 28135145, 25980754, 23056176, 26898890, 26787654, 27328445, 26979391, 27621404, 27498913, 26315354, 28528518, 28873162, 27443514)
Ambry Genetics	RCV000115633	SCV000185949	likely benign	Hereditary cancer-predisposing syndrome	2018-12-19	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Invitae	RCV000195673	SCV000252708	benign	Familial cancer of breast	2024-02-01	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000195673	SCV000427228	likely benign	Familial cancer of breast	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
Counsyl	RCV000195673	SCV000489446	likely benign	Familial cancer of breast	2016-10-11	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000115633	SCV000682782	likely benign	Hereditary cancer-predisposing syndrome	2015-02-11	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000587822	SCV000696772	benign	not provided	2016-05-03	criteria provided, single submitter	clinical testing	Variant summary: The c.33G>T (p.Gln11His) in BARD1 gene is a missense variant involves a non-conserved nucleotide and 5/5 in silico tools predict benign outcome. The variant is present in the control population dataset of ExAC at a frequency of 0.3% (115/37748 chrs tested), being most prevalent in Europeans (12/1030chrs tested), which exceeds the maximal expected allele frequency for a non-common pathogenic BARD1 variant (0.0002188). However, ExAC include a warning note that this variant is only covered in 18874 individuals (adjusted allele number = 37748). This means that the site is covered in fewer than 80% of the individuals in ExAC, which may indicate a low-quality site.The variant has been reported in affected individuals without strong evidence for causality. The variant of interest has been reported as Likely Benign/Benign by reputable databases/clinical laboratories. Taken all together, the variant was classified as Benign.
PreventionGenetics, part of Exact Sciences	RCV000587822	SCV000806127	likely benign	not provided	2017-01-30	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000587822	SCV000887591	benign	not provided	2022-06-22	criteria provided, single submitter	clinical testing
Mendelics	RCV000195673	SCV001136204	likely benign	Familial cancer of breast	2019-05-28	criteria provided, single submitter	clinical testing
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000587822	SCV002009140	likely benign	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000417369	SCV002067952	likely benign	not specified	2020-02-04	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000115633	SCV002529612	benign	Hereditary cancer-predisposing syndrome	2021-01-11	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000417369	SCV002760263	uncertain significance	not specified	2024-02-06	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000195673	SCV002807460	likely benign	Familial cancer of breast	2021-08-13	criteria provided, single submitter	clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV000195673	SCV004016367	benign	Familial cancer of breast	2023-07-07	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000195673	SCV004019256	likely benign	Familial cancer of breast	2023-02-24	criteria provided, single submitter	clinical testing	This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752].
CeGaT Center for Human Genetics Tuebingen	RCV000587822	SCV004151320	likely benign	not provided	2024-03-01	criteria provided, single submitter	clinical testing	BARD1: BS1
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003492481	SCV004240094	likely benign	Breast and/or ovarian cancer	2023-05-01	criteria provided, single submitter	clinical testing
Center of Medical Genetics and Primary Health Care	RCV001281075	SCV001451694	benign	Malignant tumor of breast		no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000587822	SCV001553371	likely benign	not provided		no assertion criteria provided	clinical testing	The BARD1 p.Gln11His variant was identified in 4 of 3420 proband chromosomes (frequency: 0.001) from individuals or families with CRC and Lynch associated cancer (Pearlman 2017, Yurgelun 2015). The variant was also identified in dbSNP (ID: rs143914387) as “with other allele”, and in the ClinVar and Clinvitae databases (as benign by Invitae and likely benign by GeneDx, Ambry Genetics, Illumina Clinical Services, Counsyl, and Quest Diagnostics Nichols Institute San Juan Capistrano). The variant was also identified in the Zhejiang Colon Cancer database 1x but no clinical information was provided. The variant was not identified in the Cosmic and MutDB databases. The variant was identified in the 1000 Genomes Project in 2 of 5000 chromosomes (frequency: 0.0004) and in the NHLBI GO Exome Sequencing Project in 19 of 7906 European American alleles (freq. 0.002). In addition, the variant was identified in control databases in 344 of 213748 chromosomes (1 homozygous) at a frequency of 0.002, increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include African in 3 of 18190 chromosomes (freq: 0.0002), Other in 16 of 5410 chromosomes (freq: 0.003), Latino in 72 of 30394 chromosomes (freq: 0.002), European Non-Finnish in 178 of 92742 chromosomes (freq: 0.002), Ashkenazi Jewish in 7 of 8982 chromosomes (freq: 0.0008), European Finnish in 57 of 16012 chromosomes (freq: 0.004), and South Asian in 11 of 26824 chromosomes (freq: 0.0004) while the variant was not observed in the East Asian population. The p.Gln11His residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000587822	SCV001799931	likely benign	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000587822	SCV001807584	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000587822	SCV001967372	likely benign	not provided		no assertion criteria provided	clinical testing