Submissions for variant NM_000465.4(BARD1):c.1883G>T (p.Cys628Phe)

gnomAD frequency: 0.00001  dbSNP: rs1227794803

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000635646	SCV000757067	uncertain significance	Familial cancer of breast	2023-11-24	criteria provided, single submitter	clinical testing	This sequence change replaces cysteine, which is neutral and slightly polar, with phenylalanine, which is neutral and non-polar, at codon 628 of the BARD1 protein (p.Cys628Phe). 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: 530051). 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.
Ambry Genetics	RCV001013517	SCV001174113	uncertain significance	Hereditary cancer-predisposing syndrome	2022-04-20	criteria provided, single submitter	clinical testing	The p.C628F variant (also known as c.1883G>T), located in coding exon 9 of the BARD1 gene, results from a G to T substitution at nucleotide position 1883. The cysteine at codon 628 is replaced by phenylalanine, an amino acid with highly dissimilar properties. This variant was observed in 1/3251 individuals who met eligibility criteria for hereditary breast and ovarian cancer syndrome (Lerner-Ellis J et al. J Cancer Res Clin Oncol, 2021 Mar;147:871-879). 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.
Color Diagnostics, LLC DBA Color Health	RCV001013517	SCV001339409	uncertain significance	Hereditary cancer-predisposing syndrome	2019-06-23	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000635646	SCV001482564	uncertain significance	Familial cancer of breast	2019-07-05	criteria provided, single submitter	clinical testing	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001357642	SCV001553169	uncertain significance	Malignant tumor of breast		no assertion criteria provided	clinical testing	The BARD1 p.Cys628Phe variant was not identified in the literature. The variant was identified in dbSNP (ID rs1227794803) as “NA” allele, and ClinVar (classified as uncertain significance by Invitae). The variant was identified in control databases in 2 of 245984 chromosomes at a frequency of 0.000008 (Genome Aggregation Database Feb 27, 2017), observed in the following population: European Non-Finnish in 2 of 111458 chromosomes (freq: 0.00002) while not observed in the African, Other, Latino, Ashkenazi Jewish, East Asian, Finnish, or South Asian populations. The variant is located within the BRCT functional domain (codons 616-653) of the BARD1 protein, which is involved in DNA repair and cell cycle regulation (Alshatwi 2012). The p.Cys628 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact of the variant to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.
PreventionGenetics, part of Exact Sciences	RCV004740379	SCV005364385	uncertain significance	BARD1-related disorder	2024-04-22	no assertion criteria provided	clinical testing	The BARD1 c.1883G>T variant is predicted to result in the amino acid substitution p.Cys628Phe. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0023% of alleles in individuals of European (Non-Finnish) descent in gnomAD and is classified as variant of uncertain significance in Clinvar (https://www.ncbi.nlm.nih.gov/clinvar/variation/530051/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.