NM_000059.4(BRCA2):c.9925G>T (p.Glu3309Ter) AND Breast-ovarian cancer, familial, susceptibility to, 2

Germline classification:: Uncertain significance (4 submissions)
Last evaluated:: Oct 12, 2023
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:: RCV000112825.17

Allele description [Variation Report for NM_000059.4(BRCA2):c.9925G>T (p.Glu3309Ter)]

NM_000059.4(BRCA2):c.9925G>T (p.Glu3309Ter)

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.9925G>T (p.Glu3309Ter)

Other names:

NM_000059.4(BRCA2):c.9925G>T; p.Glu3309Ter

HGVS:

NC_000013.11:g.32398438G>T
NG_012772.3:g.87959G>T
NM_000059.4:c.9925G>TMANE SELECT
NP_000050.2:p.Glu3309Ter
NP_000050.3:p.Glu3309Ter
LRG_293t1:c.9925G>T
LRG_293:g.87959G>T
LRG_293p1:p.Glu3309Ter
NC_000013.10:g.32972575G>T
NM_000059.3:c.9925G>T
U43746.1:n.10153G>T

Protein change:

E3309*

Links:

dbSNP: rs80359251

NCBI 1000 Genomes Browser:

rs80359251

Molecular consequence:

NM_000059.4:c.9925G>T - nonsense - [Sequence Ontology: SO:0001587]

Observations:

Condition(s)

Name:: Breast-ovarian cancer, familial, susceptibility to, 2 (BROVCA2)
Synonyms:: Breast-ovarian cancer, familial 2
Identifiers:: MONDO: MONDO:0012933; MedGen: C2675520; Orphanet: 145; OMIM: 612555

Recent activity

Clear Turn Off Turn On

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

Help

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000145733	Breast Cancer Information Core (BIC) (BRCA2)	no assertion criteria provided	Pathogenic (Apr 12, 1999)	germline	clinical testing
SCV000328177	Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	criteria provided, single submitter (CIMBA Mutation Classification guidelines May 2016)	Pathogenic (Oct 2, 2015)	germline	clinical testing	CIMBA_Mutation_Classification_guidelines_May16.pdf, Citation Link,
SCV000677709	Counsyl	criteria provided, single submitter (Counsyl Autosomal Dominant Disease Classification criteria (2015))	Likely pathogenic (Jun 5, 2017)	unknown	clinical testing	PubMed (2) [See all records that cite these PMIDs] 26332594, 18607349 Citation Link,
SCV004101448	ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel, ClinGen	reviewed by expert panel (CSpec BRCA1/2ACMG Rules Specifications V1.0)	Uncertain significance (Oct 12, 2023)	germline	curation	Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	1	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	1	not provided	not provided	not provided	clinical testing, curation
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Identification of Medically Actionable Secondary Findings in the 1000 Genomes.

Olfson E, Cottrell CE, Davidson NO, Gurnett CA, Heusel JW, Stitziel NO, Chen LS, Hartz S, Nagarajan R, Saccone NL, Bierut LJ.

PLoS One. 2015;10(9):e0135193. doi: 10.1371/journal.pone.0135193.

PubMed [citation]

PMID:: 26332594
PMCID:: PMC4558085

Mouse embryonic stem cell-based functional assay to evaluate mutations in BRCA2.

Kuznetsov SG, Liu P, Sharan SK.

Nat Med. 2008 Aug;14(8):875-81. doi: 10.1038/nm.1719. Epub 2008 Jul 6.

PubMed [citation]

PMID:: 18607349
PMCID:: PMC2640324

Details of each submission

From Breast Cancer Information Core (BIC) (BRCA2), SCV000145733.1

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

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

From Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge, SCV000328177.4

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

#	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	1	not provided

From Counsyl, SCV000677709.2

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

#	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

From ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel, ClinGen, SCV004101448.1

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

Description

The c.9925G>T variant in BRCA2 is predicted to cause a change in the length of the protein due to the insertion of a terminating codon instead of the usual Glutamic acid at amino acid 3309 (p.Glu3309Ter). This variant is absent from gnomAD v2.1 (exomes only, non-cancer subset, read depth >=25) and gnomAD v3.1 (non-cancer subset, read depth >=25) (PM2_Supporting met). Nonsense variant predicted to cause a premature stop codon that is predicted to escape nonsense mediated decay, and lead to truncation of a region with unknown protein function (sequence up to BRCA2:p.Glu3309 is maintained) (PVS1 not met). Reported by two calibrated studies with discordant results. Exhibits protein function similar to benign control variants (PMID: 29988080) and pathogenic control variants (PMID: 18607349) (PS3 and BS3 not met). In summary, this variant meets the criteria to be classified as a Variant of uncertain significance for BRCA2-related cancer predisposition based on the ACMG/AMP criteria applied as specified by the ENIGMA BRCA1/2 VCEP (PM2_Supporting).

#	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: Jun 2, 2024

ClinVar

Relating variation to medicine