NM_000059.4(BRCA2):c.2224C>T (p.Gln742Ter) AND Hereditary cancer-predisposing syndrome

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Feb 17, 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:: RCV000568409.15

Allele description [Variation Report for NM_000059.4(BRCA2):c.2224C>T (p.Gln742Ter)]

NM_000059.4(BRCA2):c.2224C>T (p.Gln742Ter)

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.2224C>T (p.Gln742Ter)

Other names:

p.Q742*:CAA>TAA

HGVS:

NC_000013.11:g.32336579C>T
NG_012772.3:g.26100C>T
NM_000059.4:c.2224C>TMANE SELECT
NP_000050.2:p.Gln742Ter
NP_000050.3:p.Gln742Ter
LRG_293t1:c.2224C>T
LRG_293:g.26100C>T
LRG_293p1:p.Gln742Ter
NC_000013.10:g.32910716C>T
NM_000059.3:c.2224C>T
U43746.1:n.2452C>T
p.Gln742*

Nucleotide change:

2452C>T

Protein change:

Q742*

Links:

dbSNP: rs80358494

NCBI 1000 Genomes Browser:

rs80358494

Molecular consequence:

NM_000059.4:c.2224C>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

Recent activity

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Homo sapiens Zic family member 3 (ZIC3), transcript variant 1, mRNA
Homo sapiens Zic family member 3 (ZIC3), transcript variant 1, mRNA
gi|1519243740|ref|NM_003413.4|

Nucleotide

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000661152	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Pathogenic (Sep 2, 2021)	germline	clinical testing	PubMed (9) [See all records that cite these PMIDs] 16030099, 18284688, 25256924, 25628955, 25716084, 26543556, 28127413, 29446198, 30630528 Citation Link,
SCV001355741	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Feb 17, 2023)	germline	clinical testing	PubMed (9) [See all records that cite these PMIDs] 16030099, 18284688, 25628955, 25716084, 26543556, 26681312, 29446198, 35875314, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000661152

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Pathogenic
(Sep 2, 2021)

germline

clinical testing

PubMed (9)
[See all records that cite these PMIDs]

Citation Link,

SCV001355741

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Feb 17, 2023)

germline

clinical testing

PubMed (9)
[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

BRCA1 germline mutations may be associated with reduced ovarian reserve.

Wang ET, Pisarska MD, Bresee C, Chen YD, Lester J, Afshar Y, Alexander C, Karlan BY.

Fertil Steril. 2014 Dec;102(6):1723-8. doi: 10.1016/j.fertnstert.2014.08.014. Epub 2014 Sep 23.

PubMed [citation]

PMID:: 25256924
PMCID:: PMC4372188

Hereditary cancer syndromes in Latino populations: genetic characterization and surveillance guidelines.

Cruz-Correa M, Pérez-Mayoral J, Dutil J, Echenique M, Mosquera R, Rivera-Román K, Umpierre S, Rodriguez-Quilichini S, Gonzalez-Pons M, Olivera MI, Pardo S; Puerto Rico Clinical Cancer Genetics Consortia..

Hered Cancer Clin Pract. 2017;15:3. doi: 10.1186/s13053-017-0063-z. Review.

PubMed [citation]

PMID:: 28127413
PMCID:: PMC5251307

See all PubMed Citations (12)

Details of each submission

From Ambry Genetics, SCV000661152.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (9)

Description

The p.Q742* pathogenic mutation (also known as c.2224C>T), located in coding exon 10 of the BRCA2 gene, results from a C to T substitution at nucleotide position 2224. This changes the amino acid from a glutamine to a stop codon within coding exon 10. This mutation has been observed in multiple Mexican probands with personal and/or family histories of breast and/or ovarian cancer (Weitzel JN et al. Cancer Epidemiol. Biomarkers Prev., 2005 Jul;14:1666-71; Lee E et al. Breast Cancer Res, 2008 Feb;10:R19; Villarreal-Garza C et al, 2015 Apr;150:389-94; Dean M et al. Gigascience, 2015 Nov;4:50; Nahleh Z et al. Am J Cancer Res, 2015 Dec;5:466-71; Cruz-Correa M et al. Hered Cancer Clin Pract, 2017 Jan;15:3; Fernández-Lopez JC et al. Hum Genomics, 2019 01;13:3). This mutation was also identified in a large, worldwide study of BRCA1/2 mutation positive families (Rebbeck TR et al. Hum Mutat, 2018 05;39:593-620). Of note, this alteration is also designated as 2452C>T in published literature. 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, SCV001355741.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (9)

Description

This variant changes 1 nucleotide in exon 11 of the BRCA2 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in at least five individuals affected with breast cancer (PMID: 18284688, 25628955, 25716084, 26543556, 26681312, 35875314) and in four suspected hereditary breast and ovarian cancer families (PMID: 16030099, 29446198). This variant has been identified in 1/251260 chromosomes 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 26, 2024

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