Submissions for variant NM_000465.4(BARD1):c.676G>C (p.Asp226His)

dbSNP: rs876659965

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000221827	SCV000276955	uncertain significance	Hereditary cancer-predisposing syndrome	2022-11-19	criteria provided, single submitter	clinical testing	The p.D226H variant (also known as c.676G>C), located in coding exon 4 of the BARD1 gene, results from a G to C substitution at nucleotide position 676. The aspartic acid at codon 226 is replaced by histidine, an amino acid with 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000230323	SCV000284974	uncertain significance	Familial cancer of breast	2024-02-01	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with histidine, which is basic and polar, at codon 226 of the BARD1 protein (p.Asp226His). This variant is not present in population databases (gnomAD no frequency). 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: 232745). 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. 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	RCV000221827	SCV000905147	uncertain significance	Hereditary cancer-predisposing syndrome	2020-01-29	criteria provided, single submitter	clinical testing	This missense variant replaces aspartic acid with histidine at codon 226 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). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has not been identified 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.
Sema4, Sema4	RCV000221827	SCV002529643	uncertain significance	Hereditary cancer-predisposing syndrome	2022-03-02	criteria provided, single submitter	curation
GeneDx	RCV002291601	SCV002584493	uncertain significance	not provided	2023-05-26	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
Myriad Genetics, Inc.	RCV000230323	SCV004189515	likely benign	Familial cancer of breast	2023-11-06	criteria provided, single submitter	clinical testing	This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752].
Baylor Genetics	RCV000230323	SCV005054585	uncertain significance	Familial cancer of breast	2024-02-27	criteria provided, single submitter	clinical testing