NM_004656.4(BAP1):c.1806G>C (p.Glu602Asp) AND BAP1-related tumor predisposition syndrome

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Jan 31, 2024
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000543121.8

Allele description [Variation Report for NM_004656.4(BAP1):c.1806G>C (p.Glu602Asp)]

NM_004656.4(BAP1):c.1806G>C (p.Glu602Asp)

Gene:

BAP1:BRCA1 associated deubiquitinase 1 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

3p21.1

Genomic location:

Preferred name:

NM_004656.4(BAP1):c.1806G>C (p.Glu602Asp)

HGVS:

NC_000003.12:g.52403222C>G
NG_031859.1:g.11772G>C
NM_004656.4:c.1806G>CMANE SELECT
NP_004647.1:p.Glu602Asp
LRG_529t1:c.1806G>C
LRG_529:g.11772G>C
NC_000003.11:g.52437238C>G
NM_004656.2:c.1806G>C
NM_004656.3:c.1806G>C

Protein change:

E602D

Links:

dbSNP: rs759423683

NCBI 1000 Genomes Browser:

rs759423683

Molecular consequence:

NM_004656.4:c.1806G>C - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: BAP1-related tumor predisposition syndrome (TPDS1)
Synonyms:: Tumor predisposition syndrome; Tumor susceptibility linked to germline BAP1 mutations; BAP1 tumor predisposition syndrome; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0013692; MedGen: C3280492; Orphanet: 289539; OMIM: 614327

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000651866	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Jan 31, 2024)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 23171164, 28492532
SCV004213222	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Sep 1, 2023)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000651866

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Jan 31, 2024)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

SCV004213222

Baylor Genetics

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Sep 1, 2023)

unknown

clinical testing

PubMed (1)
[See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Prevalence of germline BAP1 mutation in a population-based sample of uveal melanoma cases.

Aoude LG, Vajdic CM, Kricker A, Armstrong B, Hayward NK.

Pigment Cell Melanoma Res. 2013 Mar;26(2):278-9. doi: 10.1111/pcmr.12046. Epub 2012 Dec 11. No abstract available.

PubMed [citation]

PMID:: 23171164

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

See all PubMed Citations (3)

Details of each submission

From Invitae, SCV000651866.7

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

This sequence change replaces glutamic acid, which is acidic and polar, with aspartic acid, which is acidic and polar, at codon 602 of the BAP1 protein (p.Glu602Asp). This variant is present in population databases (no rsID available, gnomAD 0.007%). This missense change has been observed in individual(s) with uveal melanoma (PMID: 23171164). ClinVar contains an entry for this variant (Variation ID: 472679). 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 with a negative predictive value of 80%. 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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Baylor Genetics, SCV004213222.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Jul 15, 2024

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