NM_000059.3(BRCA2):c.9924C>G (p.Tyr3308Ter) AND Hereditary breast and ovarian cancer syndrome

This record was updated by the submitter. Please see the current version.

Germline classification:: Conflicting classifications of pathogenicity (2 submissions)
Last evaluated:: Dec 24, 2016
Review status:: criteria provided, conflicting classifications

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:: RCV000045914.6

Allele description

NM_000059.3(BRCA2):c.9924C>G (p.Tyr3308Ter)

Gene:

BRCA2:BRCA2, DNA repair associated [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

13q13.1

Genomic location:

Preferred name:

NM_000059.3(BRCA2):c.9924C>G (p.Tyr3308Ter)

HGVS:

NC_000013.11:g.32398437C>G
NG_012772.3:g.87958C>G
NM_000059.3:c.9924C>G
NP_000050.2:p.Tyr3308Ter
LRG_293t1:c.9924C>G
LRG_293:g.87958C>G
LRG_293p1:p.Tyr3308Ter
NC_000013.10:g.32972574C>G
U43746.1:n.10152C>G
p.Y3308*

Nucleotide change:

10152C>G

Protein change:

Y3308*

Links:

dbSNP: rs4987049

NCBI 1000 Genomes Browser:

rs4987049

Molecular consequence:

NM_000059.3:c.9924C>G - nonsense - [Sequence Ontology: SO:0001587]

Condition(s)

Name:: Hereditary breast and ovarian cancer syndrome (HBOC)
Synonyms:: Hereditary breast and ovarian cancer
Identifiers:: MedGen: C0677776; Orphanet: 145
Prevalence:: http://www.ncbi.nlm.nih.gov/books/NBK1247/ https://www.ncbi.nlm.nih.gov/books/NBK1247

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000073927	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Dec 24, 2016)	germline	clinical testing	Citation Link,
SCV000219428	Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario	criteria provided, single submitter (ACMG guidelines, 2007)	Likely pathogenic (Jul 9, 2013)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000073927

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Dec 24, 2016)

germline

clinical testing

Citation Link,

SCV000219428

Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario

criteria provided, single submitter

(ACMG guidelines, 2007)

Likely pathogenic
(Jul 9, 2013)

germline

clinical testing

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

Help

Summary from all submissions

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

Citations

PubMed

ACMG recommendations for standards for interpretation and reporting of sequence variations: Revisions 2007.

Richards CS, Bale S, Bellissimo DB, Das S, Grody WW, Hegde MR, Lyon E, Ward BE; Molecular Subcommittee of the ACMG Laboratory Quality Assurance Committee..

Genet Med. 2008 Apr;10(4):294-300. doi: 10.1097/GIM.0b013e31816b5cae.

PubMed [citation]

PMID:: 18414213

Details of each submission

From Invitae, SCV000073927.6

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

Description

This sequence change results in a premature translational stop signal in the last exon of the BRCA2 mRNA at codon 3308 (p.Tyr3308*). While this is not anticipated to result in nonsense mediated decay, it is expected to create a truncated BRCA2 protein. Loss-of-function variants in BRCA2 are known to be pathogenic. This particular variant has been reported in a family affected with breast and colorectal cancer (PMID: 17026620) and in an individual affected with ovarian cancer (PMID: 22711857). It is also known as 10152C>G in the literature. ClinVar contains an entry for this variant (Variation ID: 52916). While the pathogenicity of truncating variants located in this last coding exon is not clinically conclusive due to the observation of neutral truncating variants (PMID: 8896551, 18097605, 20104584), the deleterious effect of this variant has been well established in cell-based model systems that show hypersensitivity to genotoxic damage, defective homologous recombination and RAD51-mediated DNA repair, and increased chromosomal aberrations in cells carrying this variant (PMID: 18593900, 18607349). For these reasons, this variant has been classified as Pathogenic.

#	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 Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario, SCV000219428.2

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

#	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: Jul 5, 2017

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