Submissions for variant NM_000465.4(BARD1):c.1788A>G (p.Lys596=)

gnomAD frequency: 0.00004  dbSNP: rs777084777

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000195538	SCV000253275	likely benign	Familial cancer of breast	2024-01-31	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000214851	SCV000275891	likely benign	Hereditary cancer-predisposing syndrome	2015-05-28	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.
Color Diagnostics, LLC DBA Color Health	RCV000214851	SCV000682731	likely benign	Hereditary cancer-predisposing syndrome	2015-12-14	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001192856	SCV001361279	benign	not specified	2019-03-21	criteria provided, single submitter	clinical testing	Variant summary: BARD1 c.1788A>G alters a non-conserved nucleotide resulting in a synonymous change. 4/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 9.4e-05 in 276966 control chromosomes, predominantly at a frequency of 0.00076 within the Latino subpopulation in the gnomAD database. The observed variant frequency within Latino control individuals in the gnomAD database is approximately 3 fold of the estimated maximal expected allele frequency for a pathogenic variant in BARD1 causing Hereditary Breast and Ovarian Cancer phenotype (0.00025), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Latino origin. To our knowledge, no occurrence of c.1788A>G in individuals affected with Hereditary Breast and Ovarian Cancer and no experimental evidence demonstrating its impact on protein function have been reported. A co-occurrence with a likely pathogenic variant has been reported in our internal database (BRCA2 c.4218_4221delAGAA , p.Lys1406fsX3), providing supporting evidence for a benign role. Three ClinVar submissions from clinical diagnostic laboratories cite the variant as likely benign. Based on the evidence outlined above, the variant was classified as benign.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001800524	SCV002046280	benign	not provided	2020-10-09	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000214851	SCV002529548	likely benign	Hereditary cancer-predisposing syndrome	2021-11-18	criteria provided, single submitter	curation
GeneDx	RCV001800524	SCV002558386	likely benign	not provided	2018-12-17	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003907747	SCV004719923	likely benign	BARD1-related condition	2019-03-28	criteria provided, single submitter	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).