Submissions for variant NM_000465.4(BARD1):c.2212A>G (p.Ile738Val)

gnomAD frequency: 0.00745  dbSNP: rs61754118

Total submissions: 19

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000212143	SCV000167169	benign	not specified	2013-10-18	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Ambry Genetics	RCV000128965	SCV000172847	benign	Hereditary cancer-predisposing syndrome	2014-06-17	criteria provided, single submitter	clinical testing	This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, 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	RCV000205303	SCV000262392	benign	Familial cancer of breast	2024-02-01	criteria provided, single submitter	clinical testing
Vantari Genetics	RCV000128965	SCV000267000	benign	Hereditary cancer-predisposing syndrome	2015-12-18	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000128965	SCV000292113	benign	Hereditary cancer-predisposing syndrome	2014-11-19	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000205303	SCV000427203	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	RCV000205303	SCV000488652	benign	Familial cancer of breast	2016-05-25	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000205303	SCV000602629	benign	Familial cancer of breast	2023-11-22	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000212143	SCV000806121	benign	not specified	2016-11-28	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000212143	SCV000888810	benign	not specified	2020-07-24	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University of Leipzig Medical Center	RCV000205303	SCV001440199	benign	Familial cancer of breast	2019-01-01	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000212143	SCV002067942	benign	not specified	2020-09-18	criteria provided, single submitter	clinical testing
National Health Laboratory Service, Universitas Academic Hospital and University of the Free State	RCV002225403	SCV002505090	benign	Hereditary breast ovarian cancer syndrome	2022-04-19	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000128965	SCV002529589	benign	Hereditary cancer-predisposing syndrome	2021-05-11	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000212143	SCV002760231	likely benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV000205303	SCV004016359	benign	Familial cancer of breast	2023-07-07	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000205303	SCV004019253	benign	Familial cancer of breast	2023-02-24	criteria provided, single submitter	clinical testing	This variant is considered benign. This variant has been observed at a population frequency that is significantly greater than expected given the associated disease prevalence and penetrance. 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	RCV003456367	SCV004183862	benign	not provided	2024-03-01	criteria provided, single submitter	clinical testing	BARD1: BP4, BS1, BS2
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001357750	SCV001553313	benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	BARD1, EXON11, c.2212A>G, p.Ile738Val, Heterozygous, Benign The BARD1 p.Ile738Val variant was identified in 5 of 1030 proband chromosomes (frequency: 0.005) from Polish, Australian and Belgian individuals or families with high risk BRCA1/2 negative breast and/or ovarian cancer and was identified in 5 of 1096 control chromosomes (frequency:0.005) from healthy individuals (Ratajska 2012, Gorringe 2008, De Brakeleer 2010). The variant was identified in a breast tumour, and assessed to be a neutral variant based on a transient apoptosis assay that showed no loss of function (Sauer 2005). In addition, the variant is located with the BRCT functional domain(s) increasing the liklihood that it may have clinical significance; however, protein modelling showed no effect on protein structure or stability (De Brakeleer 2010). The variant was also identified in dbSBP (ID: rs61754118) “With Likely benign allele”, ClinVar (classified benign by GeneDx, Ambry Genetics, Invitae, Vantari Genetics, Color Genomics, and Counsyl; and likely benign by Illumina), Clinivitae (4X) and the Zhejiang Colon Cancer Database (5x), but was not identified in Cosmic and MutDB databases. The variant was identified in control databases in 2066 (21 homozygous) of 277076 chromosomes at a frequency of 0.007 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Consortium Feb 27, 2017); being identified in the following populations at a frequency greater than 1%: Ashkenazi Jewish* in 285 of 10150 chromosomes (freq: 0.028), Other in 119 of 6464 chromosomes (freq: 0.018), and Latino in 389 of 34408 chromosomes (freq: 0.011). The p.Ile738Val residue is not conserved in mammals and four out of five 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 this variant meets our laboratory's criteria to be classified as benign.