Submissions for variant NM_000465.4(BARD1):c.643A>T (p.Asn215Tyr)

dbSNP: rs864622353

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000206509	SCV000260263	uncertain significance	Familial cancer of breast	2021-08-30	criteria provided, single submitter	clinical testing	This variant has been observed in individual(s) with ovarian cancer (PMID: 30093976). This variant is not present in population databases (ExAC no frequency). This sequence change replaces asparagine with tyrosine at codon 215 of the BARD1 protein (p.Asn215Tyr). The asparagine residue is highly conserved and there is a large physicochemical difference between asparagine and tyrosine. ClinVar contains an entry for this variant (Variation ID: 220032). 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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive.
Ambry Genetics	RCV003165490	SCV003865641	uncertain significance	Hereditary cancer-predisposing syndrome	2022-12-01	criteria provided, single submitter	clinical testing	The p.N215Y variant (also known as c.643A>T), located in coding exon 4 of the BARD1 gene, results from an A to T substitution at nucleotide position 643. The asparagine at codon 215 is replaced by tyrosine, an amino acid with dissimilar properties. This alteration has been reported in an individual from a cohort of 1191 cancer index patients who underwent clinical evaluation and testing with multigene panels (Chan GHJ et al. Oncotarget, 2018 Jul;9:30649-30660). This variant was also 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, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Baylor Genetics	RCV000206509	SCV004217237	uncertain significance	Familial cancer of breast	2023-07-04	criteria provided, single submitter	clinical testing
GeneDx	RCV004719753	SCV005325429	uncertain significance	not provided	2024-01-09	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in an individual with ovarian cancer (PMID: 30093976); This variant is associated with the following publications: (PMID: 32885271, 30093976)
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001358496	SCV001554245	uncertain significance	Malignant tumor of breast		no assertion criteria provided	clinical testing	The BARD1 p.Asn215Tyr variant was identified in 1 of 2382 proband chromosomes (frequency: 0.0004) from individuals with primary cancer (Chan 2018, 30093976). The proband above had ovarian cancer at age 43 and a family history of breast and ovarian cancer although segregation analysis was not performed. The variant was also identified in ClinVar (as Uncertain Significance by Invitae 2016). The variant was identified in control databases in 1 of 227416 chromosomes at a frequency of 0.000004 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European Non-Finnish in 1 of 106104 chromosomes (freq: 0.000009), while the variant was not observed in the African, Other, Latino, Ashkenazi Jewish, East Asian, Finnish, and South Asian populations. The p.Asn215 residue is conserved in mammals but not in more distantly related organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume 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.