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

Germline classification:: Pathogenic (3 submissions)
Last evaluated:: Dec 24, 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:: RCV000496760.15

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 breast ovarian cancer syndrome
Synonyms:: Hereditary breast and ovarian cancer syndrome; Hereditary breast and ovarian cancer; Hereditary breast and ovarian cancer syndrome (HBOC); See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0003582; MeSH: D061325; MedGen: C0677776; Orphanet: 145

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000587625	Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto - The Canadian Open Genetics Repository (COGR)	no assertion criteria provided	Pathogenic (Jan 31, 2014)	germline	research
SCV000916834	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Feb 7, 2022)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 16030099, 18284688, 26543556, 25628955, 25716084 Citation Link,
SCV001586459	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Dec 24, 2023)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 20104584, 16030099, 18284688, 25628955, 26543556, 26681312, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000587625

Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto - The Canadian Open Genetics Repository (COGR)

no assertion criteria provided

Pathogenic
(Jan 31, 2014)

germline

research

SCV000916834

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Pathogenic
(Feb 7, 2022)

germline

clinical testing

PubMed (5)
[See all records that cite these PMIDs]

Citation Link,

SCV001586459

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Dec 24, 2023)

germline

clinical testing

PubMed (7)
[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	yes	not provided	not provided	not provided	not provided	not provided	research
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

The prevalence of BRCA1 and BRCA2 mutations among young Mexican women with triple-negative breast cancer.

Villarreal-Garza C, Weitzel JN, Llacuachaqui M, Sifuentes E, Magallanes-Hoyos MC, Gallardo L, Alvarez-Gómez RM, Herzog J, Castillo D, Royer R, Akbari M, Lara-Medina F, Herrera LA, Mohar A, Narod SA.

Breast Cancer Res Treat. 2015 Apr;150(2):389-94. doi: 10.1007/s10549-015-3312-8. Epub 2015 Feb 26.

PubMed [citation]

PMID:: 25716084
PMCID:: PMC4532439

Characterization of BRCA1 and BRCA2 deleterious mutations and variants of unknown clinical significance in unilateral and bilateral breast cancer: the WECARE study.

Borg A, Haile RW, Malone KE, Capanu M, Diep A, Törngren T, Teraoka S, Begg CB, Thomas DC, Concannon P, Mellemkjaer L, Bernstein L, Tellhed L, Xue S, Olson ER, Liang X, Dolle J, Børresen-Dale AL, Bernstein JL.

Hum Mutat. 2010 Mar;31(3):E1200-40. doi: 10.1002/humu.21202.

PubMed [citation]

PMID:: 20104584
PMCID:: PMC2928257

See all PubMed Citations (8)

Details of each submission

From Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto - The Canadian Open Genetics Repository (COGR), SCV000587625.1

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

#	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 Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000916834.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

Variant summary: BRCA2 c.2224C>T (p.Gln742X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 4e-06 in 251260 control chromosomes. c.2224C>T has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer, who were mostly of Hispanic origin (examples: Weitzel 2005, Lee 2008, Nahleh 2015, Dean 2015). Nine clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was 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 Invitae, SCV001586459.4

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

Description

This sequence change creates a premature translational stop signal (p.Gln742*) in the BRCA2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in BRCA2 are known to be pathogenic (PMID: 20104584). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with a personal and/or family history of breast and/or ovarian cancer (PMID: 16030099, 18284688, 25628955, 26543556, 26681312). ClinVar contains an entry for this variant (Variation ID: 51257). 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

Last Updated: Jun 29, 2024

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