Submissions for variant NM_000465.4(BARD1):c.1693C>T (p.Arg565Cys)

gnomAD frequency: 0.00002  dbSNP: rs587782279

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000131139	SCV000186075	uncertain significance	Hereditary cancer-predisposing syndrome	2023-06-12	criteria provided, single submitter	clinical testing	The p.R565C variant (also known as c.1693C>T), located in exon 8 of the BARD1 gene, results from a C to T substitution at nucleotide position 1693. The arginine at codon 565 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration was reported in an individual diagnosed with pancreatic cancer (Chaffee KG et al. Genet. Med. 2018 01;20(1):119-127). This alteration was found to have intermediate activity in a homology-directed DNA repair (HDR) assay (Adamovich AI et al. PLoS Genet. 2019 03;15(3):e1008049). This amino acid position is well 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.
GeneDx	RCV000481652	SCV000564695	uncertain significance	not provided	2023-06-06	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies demonstrate reduced homology-directed DNA repair activity compared to wild type (Adamovich et al., 2019); Observed in an individual with a personal and family history of pancreatic cancer (Chaffee et al., 2018); This variant is associated with the following publications: (PMID: 18842000, 30925164, 28726808)
Invitae	RCV000536917	SCV000632981	uncertain significance	Familial cancer of breast	2023-12-31	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 565 of the BARD1 protein (p.Arg565Cys). This variant is present in population databases (rs587782279, gnomAD 0.01%). This missense change has been observed in individual(s) with breast cancer and/or pancreatic cancer (PMID: 28726808; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 142170). 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. 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.
Color Diagnostics, LLC DBA Color Health	RCV000131139	SCV000682725	uncertain significance	Hereditary cancer-predisposing syndrome	2023-10-27	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with cysteine at codon 565 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). A functional study has reported that this variant results in ~50% decrease in BARD1 homology-directed DNA repair activity compared to wild type protein (PMID: 30925164). This variant has been detected in a breast cancer case-control meta-analysis in 5/60463 cases and 1/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID BARD1_000185) and also reported in an individual affected with pancreatic cancer and in two suspected hereditary breast and ovarian cancer families (PMID: 28726808, 34359559). This variant has been identified in 8/251308 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000481652	SCV001133441	uncertain significance	not provided	2018-09-13	criteria provided, single submitter	clinical testing
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000481652	SCV002009150	uncertain significance	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002281959	SCV002570615	uncertain significance	not specified	2022-07-07	criteria provided, single submitter	clinical testing	Variant summary: BARD1 c.1693C>T (p.Arg565Cys) results in a non-conservative amino acid change located in the BRCT domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.2e-05 in 251308 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1693C>T has been reported in the literature in individuals affected with Pancreatic Cancer. This report does not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome (Chaffee_2017). At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in about 50% of normal activity (Adamovich_2019). Seven 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.
Institute of Human Genetics, University of Leipzig Medical Center	RCV000536917	SCV004027669	uncertain significance	Familial cancer of breast	2023-06-13	criteria provided, single submitter	clinical testing	Criteria applied: PS3_MOD,PM2_SUP
Baylor Genetics	RCV000536917	SCV004214961	uncertain significance	Familial cancer of breast	2023-10-16	criteria provided, single submitter	clinical testing