NM_004656.4(BAP1):c.1643G>A (p.Arg548His) AND Hereditary cancer-predisposing syndrome

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Oct 13, 2023
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:: RCV000560956.10

Allele description [Variation Report for NM_004656.4(BAP1):c.1643G>A (p.Arg548His)]

NM_004656.4(BAP1):c.1643G>A (p.Arg548His)

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.1643G>A (p.Arg548His)

HGVS:

NC_000003.12:g.52403502C>T
NG_031859.1:g.11492G>A
NM_004656.4:c.1643G>AMANE SELECT
NP_004647.1:p.Arg548His
LRG_529t1:c.1643G>A
LRG_529:g.11492G>A
NC_000003.11:g.52437518C>T
NM_004656.2:c.1643G>A
NM_004656.3:c.1643G>A

Protein change:

R548H

Links:

dbSNP: rs779877855

NCBI 1000 Genomes Browser:

rs779877855

Molecular consequence:

NM_004656.4:c.1643G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Hereditary cancer-predisposing syndrome
Synonyms:: Neoplastic Syndromes, Hereditary; Tumor predisposition; Cancer predisposition; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0015356; MeSH: D009386; MedGen: C0027672

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000672780	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Uncertain significance (Oct 13, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV000682586	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Feb 21, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 28062663, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000672780

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Uncertain significance
(Oct 13, 2023)

germline

clinical testing

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

Citation Link,

SCV000682586

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Feb 21, 2023)

germline

clinical testing

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

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

Citations

PubMed

A population-based analysis of germline BAP1 mutations in melanoma.

O'Shea SJ, Robles-Espinoza CD, McLellan L, Harrigan J, Jacq X, Hewinson J, Iyer V, Merchant W, Elliott F, Harland M, Bishop DT, Newton-Bishop JA, Adams DJ.

Hum Mol Genet. 2017 Feb 15;26(4):717-728. doi: 10.1093/hmg/ddw403.

PubMed [citation]

PMID:: 28062663
PMCID:: PMC5409081

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Details of each submission

From Ambry Genetics, SCV000672780.5

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

Description

The p.R548H variant (also known as c.1643G>A), located in coding exon 13 of the BAP1 gene, results from a G to A substitution at nucleotide position 1643. The arginine at codon 548 is replaced by histidine, an amino acid with highly similar properties. In a population based study of BAP1 alterations in individuals with melanoma this alteration was detected in one individual diagnosed with cutaneous malignant melanoma at 30 (O'Shea SJ et al. Hum. Mol. Genet., 2017 Jan;). 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.

#	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 Color Diagnostics, LLC DBA Color Health, SCV000682586.5

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

Description

This missense variant replaces arginine with histidine at codon 548 of the BAP1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been performed for this variant. This variant has been reported in an individual affected with melanoma (PMID: 28062663). This variant has been identified in 3/251088 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.

#	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

Last Updated: Sep 29, 2024

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