Submissions for variant NM_000465.4(BARD1):c.2191C>G (p.Arg731Gly)

dbSNP: rs76744638

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000679341	SCV000149537	likely benign	not provided	2021-07-30	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 23056176, 26350354, 26787654, 27978560, 28301460)
Ambry Genetics	RCV000115628	SCV000186689	likely benign	Hereditary cancer-predisposing syndrome	2018-09-16	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	RCV000197435	SCV000252706	benign	Familial cancer of breast	2024-01-31	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000197435	SCV000427204	likely benign	Familial cancer of breast	2018-01-12	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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000679341	SCV000600189	benign	not provided	2022-09-28	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000115628	SCV000682763	benign	Hereditary cancer-predisposing syndrome	2015-09-22	criteria provided, single submitter	clinical testing
Counsyl	RCV000197435	SCV000786020	likely benign	Familial cancer of breast	2018-02-01	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000679341	SCV000806120	likely benign	not provided	2016-10-03	criteria provided, single submitter	clinical testing
Mendelics	RCV003492479	SCV000837942	likely benign	Hereditary cancer	2024-01-23	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV001818273	SCV002071692	benign	not specified	2021-05-25	criteria provided, single submitter	clinical testing
National Health Laboratory Service, Universitas Academic Hospital and University of the Free State	RCV002225328	SCV002505091	uncertain significance	Hereditary breast ovarian cancer syndrome	2022-04-19	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000115628	SCV002529586	likely benign	Hereditary cancer-predisposing syndrome	2021-03-14	criteria provided, single submitter	curation
Myriad Genetics, Inc.	RCV000197435	SCV004019252	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].
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003492478	SCV004240050	likely benign	Breast and/or ovarian cancer	2022-12-05	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001354852	SCV001549564	uncertain significance	Malignant tumor of breast		no assertion criteria provided	clinical testing	The BARD1 p.Arg731Gly variant was identified in 1 of 2520 proband chromosomes (frequency: 0.0004) from individuals or families with Lynch syndrome (Yurgelun 2015). In addition, a functional study of SNPs in the BARD1 gene, using bioinformatics tools (such as in silico splicing, computational pathogenicity predictions, biochemical properties, energy minimization and RMSD) identified this variant as probably deleterious (Alshatwi 2012). The variant was also identified in the following databases: dbSNP (ID: rs76744638) as “With Uncertain significance allele”, ClinVar (4x, with conflicting interpretations, as likely benign by GeneDx and Ambry, benign by Invitae, uncertain significance by Illumina), Clinvitae (4x, with conflicting interpretations, as likely benign uncertain significance and benign), Cosmic (1x, as pathogenic in esophagus carcinoma), Zhejiang Colon Cancer Database (1x, "reported as pathogenic"). The variant was not identified in MutDB, database. The variant was identified in control databases in 174 of 277038 chromosomes at a frequency of 0.0006 in the following populations: African in 171 of 24028 chromosomes (freq. 0.007), Latino in 3 of 6460 chromosomes (freq. 0.00009), increasing the likelihood that this may be a low frequency variant in certain populations of origin (Genome Aggregation Consortium Feb 27, 2017). The p.Arg731 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and 1 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.