rs1553645128

Positions:

• chr3-52404500-ATA-CTC

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

The ENST00000460680.6(BAP1):​c.1201_1203delinsGAG​(p.Tyr401Glu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y401C) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: BAP1 ENST00000460680.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6 B:1
• Conservation: PhyloP100: 4.36

Genes affected

BAP1 (HGNC:950): (BRCA1 associated protein 1) This gene belongs to the ubiquitin C-terminal hydrolase subfamily of deubiquitinating enzymes that are involved in the removal of ubiquitin from proteins. The encoded enzyme binds to the breast cancer type 1 susceptibility protein (BRCA1) via the RING finger domain of the latter and acts as a tumor suppressor. In addition, the enzyme may be involved in regulation of transcription, regulation of cell cycle and growth, response to DNA damage and chromatin dynamics. Germline mutations in this gene may be associated with tumor predisposition syndrome (TPDS), which involves increased risk of cancers including malignant mesothelioma, uveal melanoma and cutaneous melanoma. [provided by RefSeq, May 2013]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), BAP1. . Gene score misZ 2.6442 (greater than the threshold 3.09). Trascript score misZ 3.2667 (greater than threshold 3.09). GenCC has associacion of gene with BAP1-related tumor predisposition syndrome, Kury-Isidor syndrome, renal cell carcinoma.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
BAP1	NM_004656.4	c.1201_1203delinsGAG	p.Tyr401Glu	missense_variant	12/17	ENST00000460680.6	NP_004647.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
BAP1	ENST00000460680.6	c.1201_1203delinsGAG	p.Tyr401Glu	missense_variant	12/17	1	NM_004656.4	ENSP00000417132	P1
BAP1	ENST00000296288.9	c.1147_1149delinsGAG	p.Tyr383Glu	missense_variant	12/17	5		ENSP00000296288
BAP1	ENST00000490804.1	n.629_631delinsGAG		non_coding_transcript_exon_variant	2/3	2
BAP1	ENST00000469613.5			upstream_gene_variant		1		ENSP00000418320

Frequencies

GnomAD3 genomes Cov.: 33

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 33

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:6 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jun 19, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Mar 06, 2024	Observed in a healthy control, but absent from cases, in a melanoma case-control study (PMID: 28062663); Published functional studies demonstrate no damaging effect: deubiquitinase activity comparable to wild-type (PMID: 28062663); In silico analysis supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 29761599, 30039884, 23056405, 28062663) -

Hereditary cancer-predisposing syndrome Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Feb 15, 2023	The c.1201_1203delTATinsGAG variant (also known as p.Y401E), located in coding exon 12 of the BAP1 gene, results from an in-frame deletion of TAT and insertion of GAG between nucleotide positions 1201 and 1203. This results in the substitution of the tyrosine residue for the glutamic acid residue at codon 401, an amino acid with dissimilar properties. In one study, this variant was identified in 0/1977 melanoma cases and in 1/754 controls (O'Shea et al. Hum Mol Genet 2017 02;26(4):717-28). Based on data from gnomad, the p.Y401E allele has an overall frequency of approximately 0.014% (39/280040). To date, this alteration has been detected with an allele frequency of approximately 0.03% (greater than 40000 alleles tested) in our clinical cohort. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be neutral by in silico analysis (Choi Y et al. PLoS ONE. 2012; 7(10):e46688). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	May 17, 2023	This missense variant replaces tyrosine with glutamic acid at codon 401 of the BAP1 protein. Computational prediction suggests that this variant may not impact protein structure and function. 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, but has been reported in an unaffected control in a large melanoma case-control study (PMID: 28062663). 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. -

BAP1-related tumor predisposition syndrome Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 17, 2024	This sequence change replaces tyrosine, which is neutral and polar, with glutamic acid, which is acidic and polar, at codon 401 of the BAP1 protein (p.Tyr401Glu). Information on the frequency of this variant in the gnomAD database is not available, as this variant may be reported differently in the database. This variant has not been reported in the literature in individuals affected with BAP1-related conditions. ClinVar contains an entry for this variant (Variation ID: 584648). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this missense change does not substantially affect BAP1 function (PMID: 28062663). 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. -
Likely benign, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Jul 15, 2024	This variant is considered likely benign. Homozygosity has been confirmed in one or more individuals. As homozygosity for pathogenic variants in this gene is generally assumed to result in embryonic lethality, this variant is unlikely to be pathogenic. -

BAP1-related tumor predisposition syndrome;C5676925:Kury-Isidor syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Feb 07, 2022

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1553645128; hg19: chr3-52438516;