Submissions for variant NM_000465.4(BARD1):c.274A>T (p.Ile92Leu)

gnomAD frequency: 0.00001  dbSNP: rs750878896

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000205400	SCV000261531	uncertain significance	Familial cancer of breast	2024-01-18	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 92 of the BARD1 protein (p.Ile92Leu). This variant is present in population databases (rs750878896, gnomAD 0.003%). 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: 220741). 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	RCV000214932	SCV000273229	uncertain significance	Hereditary cancer-predisposing syndrome	2022-12-08	criteria provided, single submitter	clinical testing	The p.I92L variant (also known as c.274A>T), located in coding exon 3 of the BARD1 gene, results from an A to T substitution at nucleotide position 274. The isoleucine at codon 92 is replaced by leucine, an amino acid with highly 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.
GeneDx	RCV000486558	SCV000570238	uncertain significance	not provided	2016-05-09	criteria provided, single submitter	clinical testing	This variant is denoted BARD1 c.274A>T at the cDNA level, p.Ile92Leu (I92L) at the protein level, and results in the change of an Isoleucine to a Leucine (ATA>TTA). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BARD1 Ile92Leu 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 Isoleucine and Leucine share similar properties, this is considered a conservative amino acid substitution. BARD1 Ile92Leu occurs at a position where amino acids with properties similar to Isoleucine are tolerated across species and is located within the region of interaction 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 Ile92Leu is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Color Diagnostics, LLC DBA Color Health	RCV000214932	SCV001344607	uncertain significance	Hereditary cancer-predisposing syndrome	2021-08-09	criteria provided, single submitter	clinical testing	This missense variant replaces isoleucine with leucine at codon 92 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). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 3/251162 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.
Baylor Genetics	RCV000205400	SCV004217272	uncertain significance	Familial cancer of breast	2023-05-10	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV003493506	SCV004243125	uncertain significance	not specified	2024-02-06	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000205400	SCV001551982	uncertain significance	Familial cancer of breast		no assertion criteria provided	clinical testing	The BARD1 p.Ile92Leu variant was not identified in the literature. The variant was identified in dbSNP (rs750878896) as “with uncertain significance allele” and ClinVar (classified as uncertain significance by Invitae, GeneDx and Ambry Genetics). The variant was identified in control databases in 3 of 251,162 chromosomes at a frequency of 0.00001 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: South Asian in 1 of 30,608 chromosomes (freq: 0.00003), European in 2 of 113,648 chromosomes (freq: 0.00002), while the variant was not observed in the African, Latino, Ashkenazi Jewish, East Asian, Finnish and Other populations. The p.Ile92 residue is conserved in mammals but not in more distantly related organisms however four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; 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) 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.