NM_000059.4(BRCA2):c.5217_5223del (p.Thr1738_Tyr1739insTer) AND not provided

Germline classification:: Pathogenic (5 submissions)
Last evaluated:: Oct 11, 2022
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:: RCV000219434.23

Allele description [Variation Report for NM_000059.4(BRCA2):c.5217_5223del (p.Thr1738_Tyr1739insTer)]

NM_000059.4(BRCA2):c.5217_5223del (p.Thr1738_Tyr1739insTer)

Gene:

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

Variant type:

Deletion

Cytogenetic location:

13q13.1

Genomic location:

Preferred name:

NM_000059.4(BRCA2):c.5217_5223del (p.Thr1738_Tyr1739insTer)

Other names:

5445del5; 5445_5451del7

HGVS:

NC_000013.11:g.32339572_32339578del
NG_012772.3:g.29093_29099del
NM_000059.4:c.5217_5223delMANE SELECT
NP_000050.3:p.Thr1738_Tyr1739insTer
LRG_293:g.29093_29099del
NC_000013.10:g.32913709_32913715del
NC_000013.10:g.32913709_32913715delTTTAAGT
NM_000059.3:c.5217_5223del7
NM_000059.3:c.5217_5223delTTTAAGT
NM_000059.4:c.5217_5223del
U43746.1:n.5445_5451delTTTAAGT
p.Tyr1739*
p.Tyr1739fs
p.Y1739*

Nucleotide change:

5445del7

Links:

Breast Cancer Information Core (BIC) (BRCA2): 5445&base_change=del TTTAAGT; dbSNP: rs80359496

NCBI 1000 Genomes Browser:

rs80359496

Molecular consequence:

NM_000059.4:c.5217_5223del - nonsense - [Sequence Ontology: SO:0001587]

Observations:

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000278858	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Oct 11, 2022)	germline	clinical testing	Citation Link,
SCV000296636	Quest Diagnostics Nichols Institute San Juan Capistrano	criteria provided, single submitter (Quest Diagnostics criteria)	Pathogenic (Jul 3, 2022)	unknown	clinical testing	PubMed (11) [See all records that cite these PMIDs] 29339979, 30720243, 31447099, 29446198, 22776961, 26350514, 15131399, 12698193, 10717622, 26467025, 26295337
SCV000602857	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process)	Pathogenic (Apr 1, 2020)	germline	clinical testing	Citation Link,
SCV003816145	Revvity Omics, Revvity	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Aug 2, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004226576	Mayo Clinic Laboratories, Mayo Clinic	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 15, 2022)	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	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

BRCA1 and BRCA2 mutation spectrum - an update on mutation distribution in a large cancer genetics clinic in Norway.

Heramb C, Wangensteen T, Grindedal EM, Ariansen SL, Lothe S, Heimdal KR, Mæhle L.

Hered Cancer Clin Pract. 2018;16:3. doi: 10.1186/s13053-017-0085-6.

PubMed [citation]

PMID:: 29339979
PMCID:: PMC5761139

High prevalence of cancer-associated TP53 variants in the gnomAD database: A word of caution concerning the use of variant filtering.

Soussi T, Leroy B, Devir M, Rosenberg S.

Hum Mutat. 2019 May;40(5):516-524. doi: 10.1002/humu.23717. Epub 2019 Mar 28.

PubMed [citation]

PMID:: 30720243

See all PubMed Citations (12)

Details of each submission

From GeneDx, SCV000278858.11

#	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 (Malone et al., 2000; Schrader et al., 2012; Hberg-Vetti et al., 2016; Lilyquist et al., 2017; Heramb et al., 2018); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Not observed at significant frequency in large population cohorts (gnomAD); Also known as 5445del7; This variant is associated with the following publications: (PMID: 12649099, 26320393, 23242139, 16086312, 10717622, 15131399, 26295337, 26350514, 15993273, 28152038, 22776961, 29339979, 12698193, 29371908, 30720243, 30787465, 31447099, 28888541)

#	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 Quest Diagnostics Nichols Institute San Juan Capistrano, SCV000296636.4

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

Description

This frameshift variant alters the translational reading frame of the BRCA2 mRNA and causes the premature termination of BRCA2 protein synthesis. The frequency of this variant in the general population, 0.000004 (1/248722 chromosomes, http://gnomad.broadinstitute.org), is consistent with pathogenicity. In the published literature, the variant has been reported in individuals with breast cancer (PMID: 12698193 (2003), 10717622 (2000), 22776961 (2012)) and ovarian cancer (PMID: 26350514 (2015)). 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 ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories, SCV000602857.2

#	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.5217_5223del; p.Tyr1739Ter variant (rs80359496), also known as 5445del7, is reported in the literature in multiple families affected with breast and ovarian cancer syndrome (Malone 2000, Scottish/Northern Irish BRCAI/BRCA2 Consortium 2003). This variant is found on only a single chromosome in the Genome Aggregation Database (1/248722 alleles), indicating it is not a common polymorphism. This variant deletes seven nucleotides and induces an early termination codon, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on the above information, this variant is considered pathogenic. References: Malone KE et al. Frequency of BRCA1/BRCA2 mutations in a population-based sample of young breast carcinoma cases. Cancer. 2000 Mar 15;88(6):1393-402. Scottish/Northern Irish BRCAI/BRCA2 Consortium. BRCA1 and BRCA2 mutations in Scotland and Northern Ireland. Br J Cancer. 2003 Apr 22;88(8):1256-62.

#	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 Revvity Omics, Revvity, SCV003816145.2

#	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	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Mayo Clinic Laboratories, Mayo Clinic, SCV004226576.1

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

Description

PP5, PM2, 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: Jun 2, 2024

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