Submissions for variant NM_000465.4(BARD1):c.1598A>T (p.Tyr533Phe)

dbSNP: rs761673463

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000213824	SCV000276343	likely benign	Hereditary cancer-predisposing syndrome	2021-05-04	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000526059	SCV000632972	uncertain significance	Familial cancer of breast	2024-12-21	criteria provided, single submitter	clinical testing	This sequence change replaces tyrosine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 533 of the BARD1 protein (p.Tyr533Phe). RNA analysis indicates that this missense change induces altered splicing and may result in an absent or altered protein product. This variant is present in population databases (rs761673463, gnomAD no frequency). This missense change has been observed in individual(s) with breast cancer (PMID: 34326862, 36672847). ClinVar contains an entry for this variant (Variation ID: 232255). 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. Experimental studies have shown that this missense change does not substantially affect BARD1 function (PMID: 30925164). Studies have shown that this missense change results in activation of a cryptic splice site, and produces a non-functional protein and/or introduces a premature termination codon (internal data). 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.
Color Diagnostics, LLC DBA Color Health	RCV000213824	SCV001359832	uncertain significance	Hereditary cancer-predisposing syndrome	2020-11-02	criteria provided, single submitter	clinical testing	This missense variant replaces tyrosine with phenylalanine at codon 533 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). A functional study has shown that the variant protein leads to comparable homology-directed DNA repair activity to the wild-type protein in a mammalian cell-based assay (PMID: 30925164). To our knowledge, 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.
GeneDx	RCV001546645	SCV001766197	uncertain significance	not provided	2023-09-20	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 function; In silico analysis supports that this variant has a deleterious effect on splicing; Published functional studies demonstrate no damaging effect: homology-directed repair (HDR) activity similar to wild type (Adamovich et al., 2019); This variant is associated with the following publications: (PMID: 18480049, 34326862, 30925164, 36672847)
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001546645	SCV002774437	uncertain significance	not provided	2021-07-30	criteria provided, single submitter	clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV000526059	SCV005437109	uncertain significance	Familial cancer of breast	2024-12-17	criteria provided, single submitter	clinical testing	This sequence change replaces tyrosine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 533 of the BARD1 protein (p.Tyr533Phe).This amino acid position is highly conservative (PhyloP=6.3) RNA analysis indicates that this missense change induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs761673463, gnomAD no frequency). This missense change has been observed in individual(s) with breast cancer (PMID: 34326862, 36672847). ClinVar contains an entry for this variant (Variation ID: 232255). In silico analysis supports that this variant has a deleterious effect on splicing. 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.