Submissions for variant NM_000465.4(BARD1):c.233G>C (p.Cys78Ser)

dbSNP: rs199780731

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000482533	SCV000570646	uncertain significance	not provided	2016-06-14	criteria provided, single submitter	clinical testing	This variant is denoted BARD1 c.233G>C at the cDNA level, p.Cys78Ser (C78S) at the protein level, and results in the change of a Cysteine to a Serine (TGC>TCC). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BARD1 Cys78Ser was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Cysteine and Serine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BARD1 Cys78Ser occurs at a position that is conserved in mammals and is located in the RING-type Zinc finger domain as well as a region known to interact with BRCA1 (UniProt). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether BARD1 Cys78Ser is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000549884	SCV000633025	uncertain significance	Familial cancer of breast	2023-03-26	criteria provided, single submitter	clinical testing	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. Experimental studies have shown that this missense change does not substantially affect BARD1 function (PMID: 29367421). 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. ClinVar contains an entry for this variant (Variation ID: 421438). This variant has not been reported in the literature in individuals affected with BARD1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces cysteine, which is neutral and slightly polar, with serine, which is neutral and polar, at codon 78 of the BARD1 protein (p.Cys78Ser).
Color Diagnostics, LLC DBA Color Health	RCV000775784	SCV000910232	uncertain significance	Hereditary cancer-predisposing syndrome	2019-06-23	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000775784	SCV001176045	uncertain significance	Hereditary cancer-predisposing syndrome	2024-06-05	criteria provided, single submitter	clinical testing	The p.C78S variant (also known as c.233G>C), located in coding exon 3 of the BARD1 gene, results from a G to C substitution at nucleotide position 233. The cysteine at codon 78 is replaced by serine, an amino acid with dissimilar properties. This variant is located in the BARD1 RING domain but does not coordinate zinc binding. In one study, p.C78S demonstrated ability to ubiquitylate H2A on nucleosomes similar to wild type BARD1, a function necessary for homologous recombination (Stewart MD et al. Proc. Natl. Acad. Sci. U.S.A., 2018 02;115:1316-1321). This amino acid position is 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001193607	SCV001362554	uncertain significance	not specified	2019-11-26	criteria provided, single submitter	clinical testing	Variant summary: BARD1 c.233G>C (p.Cys78Ser) results in a non-conservative amino acid change located in the Zinc finger, RING-type domain of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 243944 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.233G>C in individuals affected with Breast Cancer has been reported. At least one publication reports experimental evidence evaluating an impact on protein function. These results showed no damaging effect of this variant (Stewart_2018). Three 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.
Baylor Genetics	RCV000549884	SCV004217247	uncertain significance	Familial cancer of breast	2023-06-19	criteria provided, single submitter	clinical testing