Submissions for variant NM_000465.4(BARD1):c.709C>G (p.Gln237Glu)

gnomAD frequency: 0.00005  dbSNP: rs587780035

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000587339	SCV000149550	uncertain significance	not provided	2023-05-30	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 25186949, 29292755, 25980754)
Ambry Genetics	RCV000115641	SCV000185222	likely benign	Hereditary cancer-predisposing syndrome	2019-01-22	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	RCV000205761	SCV000259456	uncertain significance	Familial cancer of breast	2024-01-24	criteria provided, single submitter	clinical testing	This sequence change replaces glutamine, which is neutral and polar, with glutamic acid, which is acidic and polar, at codon 237 of the BARD1 protein (p.Gln237Glu). This variant is present in population databases (rs587780035, gnomAD 0.02%). This missense change has been observed in individual(s) with ovarian cancer and/or suspected Lynch syndrome (PMID: 25980754, 34326862). ClinVar contains an entry for this variant (Variation ID: 127745). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The glutamic acid amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000587339	SCV000696786	uncertain significance	not provided	2016-07-11	criteria provided, single submitter	clinical testing	Variant summary: The BARD1 c.709C>G (p.Gln237Glu) variant causes a missense change involving a non-conserved nucleotide with 4/4 in silico tools (SNPs&GO not captured due to low reliability index) predict a benign outcome, although these predictions have yet to be functionally assessed. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 11/114928 (1/10448), predominantly in the European (Non-Finnish) cohort, 11/64678 (1/5878), these frequencies do not exceed the estimated maximal expected allele frequency of a pathogenic BARD1 variant (0.0002188). The variant of interest was observed in an affected individual via a publication with limited information (ie, lack of cosegregation data) not allowing for an independent evaluation. Multiple clinical laboratories have cited the variant as "uncertain signficance." Therefore, taking all available lines of evidence into consideration, the variant of interest has been classified as a "Variant of Uncertain Significance (VUS)," until additional information becomes available.
Color Diagnostics, LLC DBA Color Health	RCV000115641	SCV000910876	likely benign	Hereditary cancer-predisposing syndrome	2016-07-11	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000587339	SCV001133454	uncertain significance	not provided	2019-03-14	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000115641	SCV002529645	uncertain significance	Hereditary cancer-predisposing syndrome	2021-09-25	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV002465514	SCV002760252	uncertain significance	not specified	2023-08-15	criteria provided, single submitter	clinical testing