Submissions for variant NM_000465.4(BARD1):c.49G>A (p.Gly17Arg)

gnomAD frequency: 0.00001  dbSNP: rs746495820

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000165533	SCV000216265	uncertain significance	Hereditary cancer-predisposing syndrome	2023-11-15	criteria provided, single submitter	clinical testing	The p.G17R variant (also known as c.49G>A), located in coding exon 1 of the BARD1 gene, results from a G to A substitution at nucleotide position 49. The glycine at codon 17 is replaced by arginine, an amino acid with dissimilar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000204675	SCV000261573	uncertain significance	Familial cancer of breast	2023-12-13	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 17 of the BARD1 protein (p.Gly17Arg). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. 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: 186013). 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 disruptive. 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.
GeneDx	RCV000480154	SCV000567448	uncertain significance	not provided	2024-01-26	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; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 31036035)
Color Diagnostics, LLC DBA Color Health	RCV000165533	SCV000682792	uncertain significance	Hereditary cancer-predisposing syndrome	2023-12-11	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with arginine at codon 17 of the BARD1 protein. Computational prediction suggests that this variant may not impact protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 2/208470 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	RCV001193018	SCV001361547	uncertain significance	not specified	2023-02-13	criteria provided, single submitter	clinical testing	Variant summary: BARD1 c.49G>A (p.Gly17Arg) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 9.6e-06 in 208470 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, c.49G>A has not been reported in the literature in individuals affected with Breast Cancer. And no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Sema4, Sema4	RCV000165533	SCV002529619	uncertain significance	Hereditary cancer-predisposing syndrome	2021-11-18	criteria provided, single submitter	curation
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV000204675	SCV004015228	uncertain significance	Familial cancer of breast	2023-07-07	criteria provided, single submitter	clinical testing	For the BRAD1 variant, the sequence change replaces glycine with arginine at codon 17 of the BARD1 protein (p.Gly17Arg). The glycine residue is moderately conserved and there is a moderate physicochemical difference between glycine and arginine. This variant is present in population databases (rs746495820, ExAC 0.0004%). This variant has not been reported in the literature in individuals with BARD1-related disease. ClinVar contains an entry for this variant (Variation ID: 186013). in-silico simulators to predict the effect of missense changes on protein structure and function showed (SIFT: "deleterious" low-confidence; PolyPhen-2: "probably-damaging”). Therefore, it has been classified as a Variant of Uncertain Significance.
Baylor Genetics	RCV000204675	SCV005054589	uncertain significance	Familial cancer of breast	2024-02-21	criteria provided, single submitter	clinical testing