NM_000059.4(BRCA2):c.9380G>A (p.Trp3127Ter) AND not provided

Germline classification:: Pathogenic (4 submissions)
Last evaluated:: Feb 5, 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:: RCV000485069.18

Allele description [Variation Report for NM_000059.4(BRCA2):c.9380G>A (p.Trp3127Ter)]

NM_000059.4(BRCA2):c.9380G>A (p.Trp3127Ter)

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.9380G>A (p.Trp3127Ter)

HGVS:

NC_000013.11:g.32394812G>A
NG_012772.3:g.84333G>A
NM_000059.4:c.9380G>AMANE SELECT
NP_000050.2:p.Trp3127Ter
NP_000050.3:p.Trp3127Ter
LRG_293t1:c.9380G>A
LRG_293:g.84333G>A
LRG_293p1:p.Trp3127Ter
NC_000013.10:g.32968949G>A
NM_000059.3:c.9380G>A
U43746.1:n.9608G>A
p.Trp3127*
p.W3127*

Nucleotide change:

9608G>A

Protein change:

W3127*

Links:

dbSNP: rs80359211

NCBI 1000 Genomes Browser:

rs80359211

Molecular consequence:

NM_000059.4:c.9380G>A - nonsense - [Sequence Ontology: SO:0001587]

Observations:

Condition(s)

Synonyms:: none provided; RECLASSIFIED - ADRA2C POLYMORPHISM; RECLASSIFIED - ADRB1 POLYMORPHISM
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000296586	Quest Diagnostics Nichols Institute San Juan Capistrano	criteria provided, single submitter (Quest Diagnostics criteria)	Pathogenic (Mar 24, 2021)	unknown	clinical testing	PubMed (7) [See all records that cite these PMIDs] 29785135, 29470806, 27798748, 22752604, 17899372, 26467025, 26295337
SCV000567862	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Oct 16, 2020)	germline	clinical testing	Citation Link,
SCV002048073	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2021)	Pathogenic (Jan 20, 2021)	germline	clinical testing	Citation Link,
SCV005414170	Mayo Clinic Laboratories, Mayo Clinic	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Feb 5, 2024)	germline	clinical testing	PubMed (11) [See all records that cite these PMIDs] 22752604, 25186627, 26187060, 27798748, 29446198, 29470806, 29785135, 31723001, 32885271, 35710434, 25741868

Help

Summary from all submissions

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

Citations

PubMed

Colocalisation of predicted exonic splicing enhancers in BRCA2 with reported sequence variants.

Pettigrew CA, Wayte N, Wronski A, Lovelock PK, Spurdle AB, Brown MA.

Breast Cancer Res Treat. 2008 Jul;110(2):227-34. Epub 2007 Sep 26.

PubMed [citation]

PMID:: 17899372

A Standardized DNA Variant Scoring System for Pathogenicity Assessments in Mendelian Disorders.

Karbassi I, Maston GA, Love A, DiVincenzo C, Braastad CD, Elzinga CD, Bright AR, Previte D, Zhang K, Rowland CM, McCarthy M, Lapierre JL, Dubois F, Medeiros KA, Batish SD, Jones J, Liaquat K, Hoffman CA, Jaremko M, Wang Z, Sun W, Buller-Burckle A, et al.

Hum Mutat. 2016 Jan;37(1):127-34. doi: 10.1002/humu.22918. Epub 2015 Oct 29.

PubMed [citation]

PMID:: 26467025
PMCID:: PMC4737317

See all PubMed Citations (14)

Details of each submission

From Quest Diagnostics Nichols Institute San Juan Capistrano, SCV000296586.2

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

Description

This nonsense variant causes the premature termination of BRCA2 protein synthesis. It has been reported in individuals with breast and/or ovarian cancer in the published literature (PMID: 29785135 (2018), 29470806 (2018), 27798748 (2017), 22752604 (2012)). This variant has not been reported in large, multi-ethnic general populations. Based on the available information, this variant is classified as pathogenic.

#	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 GeneDx, SCV000567862.4

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

Description

Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Observed in individuals with a personal or family history consistent with pathogenic variants in this gene (Juwle 2012, Ricci 2014, Kwong 2016, Moran 2017); Not observed in large population cohorts (Lek 2016); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Also known as c.9608G>A; This variant is associated with the following publications: (PMID: 26187060, 25256924, 25186627, 29470806, 17899372, 22752604, 24065114, 28152038, 27798748, 28281021, 29785135, 29446198, 32885271)

#	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		not provided	not provided	not provided	not provided

From ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories, SCV002048073.1

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

Description

The BRCA2 c.9380G>A; p.Trp3127Ter variant (rs80359211) has been reported in individuals with a personal history of breast cancer and in individuals with family history of hereditary breast and ovarian cancer (Rebbeck 2018, Tung 2015, Wang 2014). The variant is reported as pathogenic by several sources in the ClinVar database (Variation ID: 38235) but is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. This variant results in a premature termination codon in the last exon of the BRCA2 gene. While this may not lead to nonsense-mediated decay, it is expected to create a truncated BRCA2 protein lacking the nuclear localization signal (Jeyasekharan 2013). Additionally, other truncating variants downstream are considered pathogenic (Variation IDs: 52826, 52888, 38260, 52831). Based on available information, this variant is considered pathogenic. References: Jeyasekharan AD et al. A cancer-associated BRCA2 mutation reveals masked nuclear export signals controlling localization. Nat Struct Mol Biol. 2013 Oct;20(10):1191-8. Rebbeck TR et al. Mutational spectrum in a worldwide study of 29,700 families with BRCA1 or BRCA2 mutations. Hum Mutat. 2018 May;39(5):593-620. Tung N et al. Frequency of mutations in individuals with breast cancer referred for BRCA1 and BRCA2 testing using next-generation sequencing with a 25-gene panel. Cancer. 2015 Jan 1;121(1):25-33. Wang ET et al. BRCA1 germline mutations may be associated with reduced ovarian reserve. Fertil Steril. 2014 Dec;102(6):1723-8.

#	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 Mayo Clinic Laboratories, Mayo Clinic, SCV005414170.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (11)

Description

PM2, PM5_strong, PVS1

#	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		1	not provided	not provided	not provided

Last Updated: Feb 25, 2025

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