Submissions for variant NM_000465.4(BARD1):c.79G>C (p.Glu27Gln)

gnomAD frequency: 0.00002  dbSNP: rs587780037

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000585925	SCV000149553	uncertain significance	not provided	2017-12-11	criteria provided, single submitter	clinical testing	This variant is denoted BARD1 c.79G>C at the cDNA level, p.Glu27Gln (E27Q) at the protein level, and results in the change of a Glutamic Acid to a Glutamine (GAA>CAA). This variant was shown through in vitro functional studies to have homology directed DNA repair activity and BARD1 protein expression similar to that of wild-type (Lee 2015). BARD1 Glu27Gln was not observed at a significant allele frequency in large population cohorts (Lek 2016). Since Glutamic Acid and Glutamine differ in some properties, this is considered a semi-conservative amino acid substitution. BARD1 Glu27Gln is located in the BRCA1 interaction domain (Fox 2008). In-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure or function. Based on currently available evidence, it is unclear whether BARD1 Glu27Gln is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics	RCV000115644	SCV000185533	likely benign	Hereditary cancer-predisposing syndrome	2018-04-18	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	RCV000204805	SCV000262423	uncertain significance	Familial cancer of breast	2024-01-28	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with glutamine, which is neutral and polar, at codon 27 of the BARD1 protein (p.Glu27Gln). This variant is present in population databases (rs587780037, gnomAD 0.009%). This missense change has been observed in individual(s) with B-cell acute lymphoblastic leukemia (PMID: 36187937). ClinVar contains an entry for this variant (Variation ID: 127748). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. Experimental studies have shown that this missense change does not substantially affect BARD1 function (PMID: 26350354). 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.
Color Diagnostics, LLC DBA Color Health	RCV000115644	SCV000682820	uncertain significance	Hereditary cancer-predisposing syndrome	2023-04-11	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with glutamine at codon 27 of the BARD1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). The mutant protein has been reported to be functional in a homology-directed DNA repair assay (PMID: 26350354). This variant has not been reported in individuals affected with hereditary cancer in the literature. In a large breast cancer case-control study, this variant has been observed in 0/60466 cases and 1/53460 controls (PMID: 33471991 - Leiden Open Variation Database DB-ID BARD1_000492). This variant has been identified in 3/233664 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000585925	SCV000696791	uncertain significance	not provided	2015-11-13	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV001818274	SCV002064742	uncertain significance	not specified	2020-08-20	criteria provided, single submitter	clinical testing	DNA sequence analysis of the BARD1 gene demonstrated a sequence change, c.79G>C, in exon 1 that results in an amino acid change, p.Glu27Gln. This sequence change does not appear to have been previously described in patients with BARD1-related disorders and been described in the gnomAD database with a low population frequency of 0.0013% (dbSNP rs587780037). The p.Glu27Gln change affects a poorly conserved amino acid residue located in a domain of the BARD1 protein that is not known to be functional. The p.Glu27Gln substitution appears to be benign using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Due to these contrasting evidences and the lack of functional studies, the clinical significance of the p.Glu27Gln change remains unknown at this time.
Baylor Genetics	RCV000204805	SCV004214998	uncertain significance	Familial cancer of breast	2023-09-20	criteria provided, single submitter	clinical testing