NM_000059.4(BRCA2):c.9925G>T (p.Glu3309Ter) AND Hereditary cancer-predisposing syndrome

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Sep 6, 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:: RCV001184568.16

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]

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
SCV001350586	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Sep 6, 2023)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 18607349, 29446198, 29988080, 25741868
SCV002691029	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Uncertain significance (Jul 6, 2023)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 18607349, 22678057, 25451944, 26332594, 29446198, 29988080, 32914019 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001350586

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Sep 6, 2023)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

SCV002691029

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Uncertain significance
(Jul 6, 2023)

germline

clinical testing

PubMed (7)
[See all records that cite these PMIDs]

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

Citations

PubMed

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

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

See all PubMed Citations (8)

Details of each submission

From Color Diagnostics, LLC DBA Color Health, SCV001350586.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

This variant changes 1 nucleotide in exon 27 of the BRCA2 gene, creating a premature translation stop signal in the last coding exon. Functional studies in mouse embryonic stem cells have provided conflicting conclusions on variant impact on the protein function (PMID 18607349, 29988080). Although both studies indicated increased sensitivity to DNA damaging agents, the mutant protein was able to complement BRCA2-deficiency and showed only partially reduced homology-directed recombination activity. This variant has been reported in an individual affected with ovarian cancer (PMID: 18607349) and has been identified in 1 family among the CIMBA participants (PMID: 29446198).. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of BRCA2 function is a known mechanism of disease (clinicalgenome.org). 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

From Ambry Genetics, SCV002691029.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (7)

Description

The p.E3309* variant (also known as c.9925G>T), located in coding exon 26 of the BRCA2 gene, results from a G to T substitution at nucleotide position 9925. This changes the amino acid from a glutamic acid to a stop codon within coding exon 26. Premature stop codons are typically deleterious in nature; however, this stop codon occurs at the 3' terminus of BRCA2 and is not expected to trigger nonsense-mediated mRNA decay. Functional studies have found conflicting evidence for this variant, with this variant being shown to cause hypersensitivity to DNA damaging agents (Kuznetsov SG et al. Nat. Med., 2008 Aug;14:875-81), but also demonstrated to maintain a high rate of homology directed repair efficiency (Mesman RLS et al. Genet. Med., 2019 02;21:293-302). Since supporting evidence is conflicting 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

Last Updated: Nov 3, 2024

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