ClinVar Miner

Submissions for variant NM_004656.4(BAP1):c.1337A>T (p.Asn446Ile)

dbSNP: rs751399960
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Color Diagnostics, LLC DBA Color Health RCV000579765 SCV000682568 uncertain significance Hereditary cancer-predisposing syndrome 2021-03-17 criteria provided, single submitter clinical testing This missense variant replaces asparagine with isoleucine at codon 446 of the BAP1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with melanoma (PMID: 25787093). This variant has been identified in 2/251434 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.
Invitae RCV000693221 SCV000821081 uncertain significance BAP1-related tumor predisposition syndrome 2023-10-12 criteria provided, single submitter clinical testing This sequence change replaces asparagine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 446 of the BAP1 protein (p.Asn446Ile). This variant is present in population databases (rs751399960, gnomAD 0.002%). This missense change has been observed in individual(s) with cutaneous melanoma (PMID: 25787093). ClinVar contains an entry for this variant (Variation ID: 489613). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt BAP1 protein function. 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 RCV000579765 SCV001171088 uncertain significance Hereditary cancer-predisposing syndrome 2023-05-10 criteria provided, single submitter clinical testing The p.N446I variant (also known as c.1337A>T), located in coding exon 13 of the BAP1 gene, results from an A to T substitution at nucleotide position 1337. The asparagine at codon 446 is replaced by isoleucine, an amino acid with dissimilar properties. This alteration has been reported in a cohort of 1,109 individuals from cutaneous melanoma families (Aoude LG et al. Twin Res Hum Genet, 2015 Apr;18:126-33). 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.

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