Submissions for variant NM_000465.4(BARD1):c.1793C>T (p.Thr598Ile)

dbSNP: rs376256852

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000130644	SCV000185523	uncertain significance	Hereditary cancer-predisposing syndrome	2022-05-09	criteria provided, single submitter	clinical testing	The p.T598I variant (also known as c.1793C>T), located in coding exon 8 of the BARD1 gene, results from a C to T substitution at nucleotide position 1793. The threonine at codon 598 is replaced by isoleucine, an amino acid with similar properties. This alteration was reported in a family with multiple cases of breast cancer; however, the alteration did not segregate with breast cancer in this family (Gorringe KL et al. Breast Cancer Res Treat, 2008 Oct;111:505-9). This alteration was found to be functionally intermediate in a homology-directed DNA repair (HDR) assay (Adamovich AI et al. PLoS Genet, 2019 03;15:e1008049). In a multi-gene panel study of patients with bilateral breast cancer, this variant was observed in 1/139 cases (Fanale D et al. Cancers (Basel), 2020 Aug;12:). This amino acid position is poorly 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.
Invitae	RCV000230852	SCV000284928	uncertain significance	Familial cancer of breast	2024-01-19	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 598 of the BARD1 protein (p.Thr598Ile). This variant is present in population databases (rs376256852, gnomAD 0.003%). This missense change has been observed in individual(s) with breast cancer (PMID: 17972171, 32854451). ClinVar contains an entry for this variant (Variation ID: 141929). 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 affects BARD1 function (PMID: 30925164). 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	RCV000487282	SCV000566162	uncertain significance	not provided	2023-01-05	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies are inconclusive: intermediate effect on homology-directed repair activity (Adamovich et al., 2019); This variant is associated with the following publications: (PMID: 23056176, 32854451, 32726901, 17972171, 35650591, 17550235, 35402282, 35912549, 30925164)
Color Diagnostics, LLC DBA Color Health	RCV000130644	SCV000682733	uncertain significance	Hereditary cancer-predisposing syndrome	2023-01-23	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with isoleucine at codon 598 of the BARD1 protein. Computational prediction tool suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). A functional study has reported the mutant protein to exhibit partially reduced homology-directed DNA repair activity (PMID: 30925164). This variant has been reported in two individuals affected with breast cancer (PMID: 17972171, 32854451). In one of these families, this variant was not detected in other family members affected with breast cancer and colorectal cancer (PMID: 17972171). This variant has been identified in 2/251232 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.
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV000230852	SCV004015224	uncertain significance	Familial cancer of breast	2023-07-07	criteria provided, single submitter	clinical testing	The p.T598I variant (also known as c.1793C>T), located in coding exon 8 of the BARD1 gene, results from a C to T substitution at nucleotide position 1793. The threonine at codon 598 is replaced by isoleucine, an amino acid with similar properties. This alteration was reported in a family with multiple cases of breast cancer; however, the alteration did not segregate with breast cancer in this family (Gorringe KL et al. Breast Cancer Res. Treat. 2008 Oct;111:505-9). In a homology-directed repair (HDR) assay, this alteration showed HDR activity just below the cutoff for proficiency (Adamovich AI et al. PLoS Genet., 2019 03;15:e1008049). In addition, in silico analysis showed Benign computational verdict based on 11 benign predictions from BayesDel_addAF, DANN, DEOGEN2, EIGEN, FATHMM-MKL and 6 more vs 2 pathogenic predictions from M-CAP and MutationAssessor and the position is not strongly conserved (GERP++ rejected substitutions = 2.18 is less than 5.5). This variant has an entry in ClinVar (141929) with 4 submissions, all of which list this variant as “uncertain significance”. Also, this variant was not found in gnomAD genomes. Therefore, this variant is classified as uncertain significance.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV003320571	SCV004024843	uncertain significance	not specified	2023-08-15	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000487282	SCV004151315	uncertain significance	not provided	2023-07-01	criteria provided, single submitter	clinical testing	BARD1: PM2, BP4
Baylor Genetics	RCV000230852	SCV004217181	uncertain significance	Familial cancer of breast	2023-08-31	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000487282	SCV004234615	uncertain significance	not provided	2023-09-26	criteria provided, single submitter	clinical testing