Submissions for variant NM_000465.4(BARD1):c.1963G>C (p.Glu655Gln)

gnomAD frequency: 0.00001  dbSNP: rs786203772

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000167221	SCV000218058	uncertain significance	Hereditary cancer-predisposing syndrome	2023-08-28	criteria provided, single submitter	clinical testing	The p.E655Q variant (also known as c.1963G>C), located in coding exon 10 of the BARD1 gene, results from a G to C substitution at nucleotide position 1963. The glutamic acid at codon 655 is replaced by glutamine, an amino acid with highly similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
GeneDx	RCV000481774	SCV000567506	uncertain significance	not provided	2023-02-23	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with breast cancer (Chen et al., 2020); This variant is associated with the following publications: (PMID: 32091409)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000800715	SCV000940445	uncertain significance	Familial cancer of breast	2023-12-31	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 655 of the BARD1 protein (p.Glu655Gln). This variant is present in population databases (rs786203772, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with BARD1-related conditions. ClinVar contains an entry for this variant (Variation ID: 187488). 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 glutamine 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.
Color Diagnostics, LLC DBA Color Health	RCV000167221	SCV001342794	uncertain significance	Hereditary cancer-predisposing syndrome	2019-06-21	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001354614	SCV001549271	uncertain significance	Familial pancreatic carcinoma		no assertion criteria provided	clinical testing	The BARD1 p.Glu655Gln variant was not identified in the literature. The variant was identified in dbSNP (rs786203772) as “with uncertain significance allele” and ClinVar (classified as uncertain significance by Ambry Genetics and GeneDx). The variant was identified in control databases in 3 of 277,104 chromosomes at a frequency of 0.00001 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: East Asian in 3 of 18,870 chromosomes (freq: 0.0002), but not in the African, Other, Latino, European, Ashkenazi Jewish, Finnish, and South Asian populations. The p.Glu655 residue is not conserved in mammals and 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) do not predict a difference in splicing. 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.