NM_004656.4(BAP1):c.783+2T>C AND Hereditary cancer-predisposing syndrome

Clinical significance:Conflicting interpretations of pathogenicity, Likely pathogenic(1);Uncertain significance(1) (Last evaluated: Feb 3, 2021)

Review status:1 star out of maximum of 4 stars

criteria provided, conflicting interpretations

Based on:
2 submissions [Details]
Record status:

Allele description [Variation Report for NM_004656.4(BAP1):c.783+2T>C]


BAP1:BRCA1 associated protein 1 [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
Genomic location:
Preferred name:
  • NC_000003.12:g.52406251A>G
  • NG_031859.1:g.8743T>C
  • NM_004656.4:c.783+2T>CMANE SELECT
  • LRG_529t1:c.783+2T>C
  • LRG_529:g.8743T>C
  • NC_000003.11:g.52440267A>G
  • NM_004656.2:c.783+2T>C
  • NM_004656.3:c.783+2T>C
dbSNP: rs774730309
NCBI 1000 Genomes Browser:
Molecular consequence:
  • NM_004656.4:c.783+2T>C - splice donor variant - [Sequence Ontology: SO:0001575]


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

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
SCV000682645Color Health, Inccriteria provided, single submitter
Likely pathogenic
(Feb 3, 2021)
germlineclinical testing

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

SCV001189319Ambry Geneticscriteria provided, single submitter
Uncertain significance
(Feb 26, 2020)
germlineclinical testing

PubMed (3)
[See all records that cite these PMIDs]

Citation Link

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknown1not providednot provided1not providedclinical testing



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]

Analysis of the exome aggregation consortium (ExAC) database suggests that the BAP1-tumor predisposition syndrome is underreported in cancer patients.

Massengill JB, Sample KM, Pilarski R, McElroy J, Davidorf FH, Cebulla CM, Abdel-Rahman MH.

Genes Chromosomes Cancer. 2018 Sep;57(9):478-481. doi: 10.1002/gcc.7. Epub 2018 Jul 30.

PubMed [citation]
See all PubMed Citations (4)

Details of each submission

From Color Health, Inc, SCV000682645.4

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)


This variant causes a T to C nucleotide substitution at the +2 position of intron 9 of the BAP1 gene. Splice site prediction tools suggest that this variant may have a significant impact on RNA splicing. Although this prediction has not been confirmed in published RNA studies, this variant is expected to result in an absent or disrupted protein product. This variant has been reported in individuals affected with mesothelioma (PMID: 30338612) and breast cancer (PMID: 30980208; Color internal data). This variant has also been identified in 2/251252 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of BAP1 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Likely Pathogenic.

OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From Ambry Genetics, SCV001189319.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical testing PubMed (3)


The c.783+2T>C intronic variant results from a T to C substitution two nucleotides after coding exon 9 in the BAP1 gene. This alteration has been reported in the literature in one individual diagnosed with malignant pleural mesothelioma, as well as in a large cohort of cancer patients (Betti M et al. Genes Chromosomes Cancer. 2018 11;57:573-583; Massengill JB et al. Genes Chromosomes Cancer. 2018 09;57:478-481). However, this alteration has also been observed in many individuals who do not have a personal or family history that is consistent with or suggestive of BAP1-associated disease (Ambry internal data; Bernstein-Molho R et al. Breast Cancer Res. Treat., 2019 Jul;176:165-170). This nucleotide position is highly conserved in available vertebrate species. Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to weaken the native splice donor site efficiency. RNA studies have demonstrated that this alteration does not abolish the use of the native splice acceptor and low-level use of an upstream cryptic acceptor is predicted to lead to an in frame loss of amino acids with no known function (Ambry internal data). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknown1not providednot provided1not providednot providednot provided

Last Updated: Sep 24, 2021

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