Submissions for variant NM_000465.4(BARD1):c.1060T>A (p.Ser354Thr)

dbSNP: rs863224670

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000198033	SCV000254564	uncertain significance	Familial cancer of breast	2024-11-28	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with threonine, which is neutral and polar, at codon 354 of the BARD1 protein (p.Ser354Thr). 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: 216437). 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.
Ambry Genetics	RCV000214176	SCV000276781	uncertain significance	Hereditary cancer-predisposing syndrome	2023-04-28	criteria provided, single submitter	clinical testing	The p.S354T variant (also known as c.1060T>A), located in coding exon 4 of the BARD1 gene, results from a T to A substitution at nucleotide position 1060. The serine at codon 354 is replaced by threonine, 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.
Color Diagnostics, LLC DBA Color Health	RCV000214176	SCV000688090	uncertain significance	Hereditary cancer-predisposing syndrome	2020-07-27	criteria provided, single submitter	clinical testing	This missense variant replaces serine with threonine at codon 354 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	RCV000214176	SCV002526977	uncertain significance	Hereditary cancer-predisposing syndrome	2021-11-15	criteria provided, single submitter	curation
GeneDx	RCV003327379	SCV004034934	uncertain significance	not provided	2023-03-10	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; This variant is associated with the following publications: (PMID: 28569743)
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001357819	SCV001553404	uncertain significance	Malignant tumor of breast		no assertion criteria provided	clinical testing	The BARD1 p.Ser354Thr variant was not identified in the literature, nor was it identified in the Cosmic, MutDB, or Zhejiang Colon Cancer Database. The variant was identified in dbSNP (ID: rs863224670) as “With Uncertain significance allele”, and in the ClinVar and Clinvitae databases as uncertain significance (Ambry Genetics and Invitae). The variant was not identified in the 1000 Genomes Project, the NHLBI GO Exome Sequencing Project or the Exome Aggregation Consortium (August 8th 2016) control databases. The p.Ser354Thr residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) 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	RCV003401081	SCV004110350	uncertain significance	BARD1-related disorder	2024-06-24	no assertion criteria provided	clinical testing	The BARD1 c.1060T>A variant is predicted to result in the amino acid substitution p.Ser354Thr. To our knowledge, this variant has not been reported in the literature or in gnomAD, indicating this variant is rare. It is reported as a variant of uncertain significance in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/216437/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.