NM_000059.4(BRCA2):c.-40+2T>C AND Hereditary breast ovarian cancer syndrome

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: May 3, 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:: RCV000797145.8

Allele description [Variation Report for NM_000059.4(BRCA2):c.-40+2T>C]

NM_000059.4(BRCA2):c.-40+2T>C

Genes:

BRCA2:BRCA2 DNA repair associated [Gene - OMIM - HGNC]
LOC106721785:BRCA2 promoter/silencer region [Gene]

Variant type:

single nucleotide variant

Cytogenetic location:

13q13.1

Genomic location:

Preferred name:

NM_000059.4(BRCA2):c.-40+2T>C

HGVS:

NC_000013.11:g.32315669T>C
NG_012772.3:g.5190T>C
NG_017006.2:g.4695A>G
NG_044973.1:g.1211T>C
NM_000059.4:c.-40+2T>CMANE SELECT
NM_001406719.1:c.-40+2T>C
NM_001406720.1:c.-40+2T>C
NM_001406721.1:c.-40+2T>C
NM_001406722.1:c.-303+2T>C
LRG_293t1:c.-40+2T>C
LRG_293:g.5190T>C
NC_000013.10:g.32889806T>C
NM_000059.3:c.-40+2T>C

Links:

dbSNP: rs1593879845

NCBI 1000 Genomes Browser:

rs1593879845

Molecular consequence:

NM_000059.4:c.-40+2T>C - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001406719.1:c.-40+2T>C - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001406720.1:c.-40+2T>C - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001406721.1:c.-40+2T>C - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001406722.1:c.-303+2T>C - splice donor variant - [Sequence Ontology: SO:0001575]

Condition(s)

Name:: Hereditary breast ovarian cancer syndrome
Synonyms:: Hereditary breast and ovarian cancer syndrome; Hereditary breast and ovarian cancer; Hereditary breast and ovarian cancer syndrome (HBOC); See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0003582; MeSH: D061325; MedGen: C0677776; Orphanet: 145

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membrane glycoprotein E3 CR1-alpha [Human mastadenovirus F]
membrane glycoprotein E3 CR1-alpha [Human mastadenovirus F]
gi|9626579|ref|NP_040869.1|

Protein

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000936688	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Dec 23, 2021)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 17576681, 9536098, 28492532
SCV005184352	German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne	criteria provided, single submitter (ClinGen BRCA2 V1.0.0)	Uncertain significance (May 3, 2024)	germline	curation	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000936688

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Dec 23, 2021)

germline

clinical testing

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

SCV005184352

German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne

criteria provided, single submitter

(ClinGen BRCA2 V1.0.0)

Uncertain significance
(May 3, 2024)

germline

curation

Citation Link

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	germline	not provided	not provided	not provided	not provided	not provided	not provided	curation

Citations

PubMed

Aberrant 5' splice sites in human disease genes: mutation pattern, nucleotide structure and comparison of computational tools that predict their utilization.

Buratti E, Chivers M, Královicová J, Romano M, Baralle M, Krainer AR, Vorechovsky I.

Nucleic Acids Res. 2007;35(13):4250-63. Epub 2007 Jun 18.

PubMed [citation]

PMID:: 17576681
PMCID:: PMC1934990

Statistical features of human exons and their flanking regions.

Zhang MQ.

Hum Mol Genet. 1998 May;7(5):919-32.

PubMed [citation]

PMID:: 9536098

See all PubMed Citations (3)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000936688.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

ClinVar contains an entry for this variant (Variation ID: 643446). 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. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant has not been reported in the literature in individuals affected with BRCA2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change falls in intron 1 of the BRCA2 gene. It does not directly change the encoded amino acid sequence of the BRCA2 protein. It affects a nucleotide within the consensus splice site.

#	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 German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne, SCV005184352.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	not provided

Description

According to the ClinGen ENIGMA BRCA2 v1.0.0 criteria we chose these criteria: PS1 (supporting pathogenic): BRCA2 c.-40+1G>A was identified in trans in a patient with Fanconi Anemia; RNA studies have demonstrated that this alteration results a similar transcript pattern as is described for close match BRCA2 c.-40+1G>A in the set of samples tested (Ambry internal data)., PM2 (supporting pathogenic): Absent from controls, PM3 (medium pathogenic): Fanconi Anemia (FA) in Berlin 2 siblings compound heterozygous with FA in childhood

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

Last Updated: Sep 29, 2024

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