NM_000059.4(BRCA2):c.9018C>A (p.Tyr3006Ter) AND Hereditary cancer-predisposing syndrome

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Apr 1, 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:: RCV000131053.18

Allele description [Variation Report for NM_000059.4(BRCA2):c.9018C>A (p.Tyr3006Ter)]

NM_000059.4(BRCA2):c.9018C>A (p.Tyr3006Ter)

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.9018C>A (p.Tyr3006Ter)

HGVS:

NC_000013.11:g.32379814C>A
NG_012772.3:g.69335C>A
NM_000059.4:c.9018C>AMANE SELECT
NP_000050.2:p.Tyr3006Ter
NP_000050.3:p.Tyr3006Ter
LRG_293t1:c.9018C>A
LRG_293:g.69335C>A
LRG_293p1:p.Tyr3006Ter
NC_000013.10:g.32953951C>A
NM_000059.3:c.9018C>A
U43746.1:n.9246C>A
p.Y3006*

Protein change:

Y3006*

Links:

dbSNP: rs80359154

NCBI 1000 Genomes Browser:

rs80359154

Molecular consequence:

NM_000059.4:c.9018C>A - 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
SCV000185983	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Pathogenic (Apr 1, 2024)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV000684016	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Dec 21, 2022)	germline	clinical testing	PubMed (11) [See all records that cite these PMIDs] 12955716, 18176857, 20033483, 26026974, 29020732, 29446198, 29673794, 29884136, 32073954, 33471991, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000185983

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Pathogenic
(Apr 1, 2024)

germline

clinical testing

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

Citation Link,

SCV000684016

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Dec 21, 2022)

germline

clinical testing

PubMed (11)
[See all records that cite these PMIDs]

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

Analysis of BRCA1 and BRCA2 genes in Spanish breast/ovarian cancer patients: a high proportion of mutations unique to Spain and evidence of founder effects.

Díez O, Osorio A, Durán M, Martinez-Ferrandis JI, de la Hoya M, Salazar R, Vega A, Campos B, Rodríguez-López R, Velasco E, Chaves J, Díaz-Rubio E, Jesús Cruz J, Torres M, Esteban E, Cervantes A, Alonso C, San Román JM, González-Sarmiento R, Miner C, Carracedo A, Eugenia Armengod M, et al.

Hum Mutat. 2003 Oct;22(4):301-12.

PubMed [citation]

PMID:: 12955716

Genetic analysis of BRCA1 and BRCA2 in breast/ovarian cancer families from Aragon (Spain): two novel truncating mutations and a large genomic deletion in BRCA1.

Miramar MD, Calvo MT, Rodriguez A, Antón A, Lorente F, Barrio E, Herrero A, Burriel J, García de Jalón A.

Breast Cancer Res Treat. 2008 Nov;112(2):353-8. doi: 10.1007/s10549-007-9868-1. Epub 2008 Jan 4.

PubMed [citation]

PMID:: 18176857

See all PubMed Citations (11)

Details of each submission

From Ambry Genetics, SCV000185983.9

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

Description

The p.Y3006* pathogenic mutation (also known as c.9018C>A), located in coding exon 22 of the BRCA2 gene, results from a C to A substitution at nucleotide position 9018. This changes the amino acid from a tyrosine to a stop codon within coding exon 22. This mutation, also designated as 9246C>A, has been reported in two unrelated Spanish families with breast and ovarian cancer histories (Díez O et al. Hum Mutat, 2003 Oct;22:301-12). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.

#	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 Color Diagnostics, LLC DBA Color Health, SCV000684016.4

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

Description

This variant changes 1 nucleotide in exon 23 of the BRCA2 gene, creating a premature translation stop signal. This variant is also known as 9246C>A in the literature. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in more than 10 individuals affected with breast, ovarian, or pancreatic cancer (PMID: 18176857, 26026974, 29020732, 29673794, 29884136, 32073954, 33471991). This variant has also been reported in several suspected HBOC families, including 19 families among CIMBA participants (PMID: 12955716, 20033483, 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). Based on the available evidence, this variant is 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

Last Updated: Oct 20, 2024

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