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NM_000059.4(BRCA2):c.9117G>A (p.Pro3039=) AND BRCA2-related cancer predisposition

Germline classification:
Pathogenic (1 submission)
Last evaluated:
Jun 11, 2024
Review status:
3 stars out of maximum of 4 stars
reviewed by expert panel
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:
RCV004566785.1

Allele description [Variation Report for NM_000059.4(BRCA2):c.9117G>A (p.Pro3039=)]

NM_000059.4(BRCA2):c.9117G>A (p.Pro3039=)

Gene:
BRCA2:BRCA2 DNA repair associated [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
13q13.1
Genomic location:
Preferred name:
NM_000059.4(BRCA2):c.9117G>A (p.Pro3039=)
Other names:
P3039P; p.P3039P:CCG>CCA; NM_000059.4(BRCA2):c.9117G>A; p.Pro3039=
HGVS:
  • NC_000013.11:g.32379913G>A
  • NG_012772.3:g.69434G>A
  • NM_000059.4:c.9117G>AMANE SELECT
  • NP_000050.2:p.Pro3039=
  • NP_000050.3:p.Pro3039=
  • LRG_293t1:c.9117G>A
  • LRG_293:g.69434G>A
  • LRG_293p1:p.Pro3039=
  • NC_000013.10:g.32954050G>A
  • NM_000059.3:c.9117G>A
  • U43746.1:n.9345G>A
  • p.P3039P
Nucleotide change:
9345G>A
Links:
dbSNP: rs28897756
NCBI 1000 Genomes Browser:
rs28897756
Molecular consequence:
  • NM_000059.4:c.9117G>A - synonymous variant - [Sequence Ontology: SO:0001819]

Condition(s)

Name:
BRCA2-related cancer predisposition
Identifiers:
MONDO: MONDO:0700269; MedGen: CN377758

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Assertion and evidence details

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Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV004101443ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel, ClinGen
reviewed by expert panel

(CSpec BRCA1/2ACMG Rules Specifications V1.0)		Pathogenic
(Jun 11, 2024) 		germlinecuration

Citation Link

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Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedcuration

Details of each submission

From ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel, ClinGen, SCV004101443.3

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedcurationnot provided

Description

The c.9117G>A variant in BRCA2 is a synonymous variant (p.Pro3039=). This variant is present in gnomAD v2.1 (exomes only, non-cancer subset) or gnomAD v3.1 (non-cancer subset) but is below the ENIGMA BRCA1/2 VCEP threshold >0.00002 for BS1_Supporting (PM2_Supporting, BS1, and BA1 are not met). This variant is reported to result in aberrant mRNA splicing. RT-PCR and Mini-gene assays demonstrated that the variant impacts splicing by exon skipping (PMIDs: 17011978, 23451180, 22505045, 31843900, 32398771, 22632462). Appropriate code strength determined by comparison of results to PVS1 decision tree (PVS1 (RNA) met). Multifactorial likelihood ratio analysis using clinically calibrated data produced a combined LR for this variant of 3364.725 (based on Co-occurrence LR=2.231; Family History LR=1508.137), above the threshold for Very strong evidence towards pathogenicity (LR >350) (PP4_Very Strong met; PMID: 17924331, 31853058). In summary, this variant meets the criteria to be classified as a Pathogenic variant for BRCA2-related cancer predisposition based on the ACMG/AMP criteria applied as specified by the ENIGMA BRCA1/2 VCEP (PVS1 (RNA), PP4_VeryStrong).

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

Last Updated: Nov 24, 2024