NM_000059.4(BRCA2):c.5290_5291del (p.Ser1764fs) AND not provided

Germline classification:: Pathogenic (3 submissions)
Last evaluated:: Mar 15, 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:: RCV000481345.17

Allele description [Variation Report for NM_000059.4(BRCA2):c.5290_5291del (p.Ser1764fs)]

NM_000059.4(BRCA2):c.5290_5291del (p.Ser1764fs)

Gene:

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

Variant type:

Microsatellite

Cytogenetic location:

13q13.1

Genomic location:

Preferred name:

NM_000059.4(BRCA2):c.5290_5291del (p.Ser1764fs)

HGVS:

NC_000013.10:g.32913778_32913779del
NC_000013.11:g.32339641TC[2]
NG_012772.3:g.29162TC[2]
NM_000059.4:c.5290_5291delMANE SELECT
NP_000050.3:p.Ser1764fs
LRG_293:g.29162TC[2]
NC_000013.10:g.32913778TC[2]
NC_000013.10:g.32913778_32913779del
NC_000013.10:g.32913782_32913783delTC
NC_000013.11:g.32339645_32339646delTC
NM_000059.3:c.5290_5291delTC
NM_000059.4:c.5290_5291del
U43746.1:n.5518_5519delTC
p.Ser1764Lysfs*3

Nucleotide change:

5518delTC

Protein change:

S1764fs

Links:

Breast Cancer Information Core (BIC) (BRCA2): 5518&base_change=del TC; dbSNP: rs80359503

NCBI 1000 Genomes Browser:

rs80359503

Molecular consequence:

NM_000059.4:c.5290_5291del - frameshift variant - [Sequence Ontology: SO:0001589]

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
SCV000566976	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Jan 19, 2022)	germline	clinical testing	Citation Link,
SCV000600637	Quest Diagnostics Nichols Institute San Juan Capistrano	criteria provided, single submitter (Quest Diagnostics criteria)	Pathogenic (Mar 15, 2022)	unknown	clinical testing	PubMed (11) [See all records that cite these PMIDs] 11972384, 23479189, 24504028, 12655515, 15131399, 24728189, 29446198, 33471991, 30078507, 33087929, 26467025
SCV001549723	Department of Pathology and Laboratory Medicine, Sinai Health System - The Canadian Open Genetics Repository (COGR) See additional submitters Franklin by Genoox	no assertion criteria provided	Pathogenic	unknown	clinical testing

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000566976

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Pathogenic
(Jan 19, 2022)

germline

clinical testing

Citation Link,

SCV000600637

Quest Diagnostics Nichols Institute San Juan Capistrano

criteria provided, single submitter

(Quest Diagnostics criteria)

Pathogenic
(Mar 15, 2022)

unknown

clinical testing

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

SCV001549723

Department of Pathology and Laboratory Medicine, Sinai Health System - The Canadian Open Genetics Repository (COGR)

See additional submitters

no assertion criteria provided

Pathogenic

unknown

clinical testing

Help

Summary from all submissions

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

Citations

PubMed

Contribution of BRCA1 and BRCA2 to familial ovarian cancer: a gynecologic oncology group study.

Reedy M, Gallion H, Fowler JM, Kryscio R, Smith SA.

Gynecol Oncol. 2002 May;85(2):255-9.

PubMed [citation]

PMID:: 11972384

Novel and recurrent BRCA1/BRCA2 mutations in early onset and familial breast and ovarian cancer detected in the Program of Genetic Counseling in Cancer of Valencian Community (eastern Spain). Relationship of family phenotypes with mutation prevalence.

de Juan Jiménez I, García Casado Z, Palanca Suela S, Esteban Cardeñosa E, López Guerrero JA, Segura Huerta Á, Chirivella González I, Sánchez Heras AB, Juan Fita MJ, Tena García I, Guillen Ponce C, Martínez de Dueñas E, Romero Noguera I, Salas Trejo D, Goicoechea Sáez M, Bolufer Gilabert P.

Fam Cancer. 2013 Dec;12(4):767-77. doi: 10.1007/s10689-013-9622-2.

PubMed [citation]

PMID:: 23479189

See all PubMed Citations (11)

Details of each submission

From GeneDx, SCV000566976.6

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

Description

Frameshift 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; 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); Observed in individuals with personal or family history of BRCA2-related cancers (Reedy 2002, Kauff 2003, Lubinski 2004, Song 2014, Li 2018); Also known as 5518delTC and 5514delTC; This variant is associated with the following publications: (PMID: 15131399, 11972384, 23479189, 24728189, 24504028, 12655515, 30720243, 30078507, 30309722, 30787465, 33087929)

#	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, SCV000600637.4

#	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, 0.0000088 (1/113118 chromosomes, http://gnomad.broadinstitute.org), is consistent with pathogenicity. In the published literature, the variant has been reported in multiple individuals with hereditary breast (PMID: 15131399 (2004), 23479189 (2013), 33471991 (2021)) or ovarian cancer (PMID: 11972384 (2002), 24504028 (2014), 24728189 (2014), 30078507 (2018)). 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 Department of Pathology and Laboratory Medicine, Sinai Health System - The Canadian Open Genetics Repository (COGR), SCV001549723.1

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

Description

The BRCA2, p.Ser1764LysfsX3 variant was identified in 1 of 52 proband chromosomes (frequency: 0.02) from individuals or families with ovarian cancer (Reedy 2002). The variant was also identified in dbSNP (ID: rs80359503) as â€šÃ„ÃºWith Pathogenic alleleâ€šÃ„Ã¹, Clinvitae database (classified as pathogenic by ClinVar), ARUP Laboratories BRCA Mutations Database (classified as definitely pathogenic), the BIC database (2X with clinical importance), and UMD (1X with a â€šÃ„Ãºcausalâ€šÃ„Ã¹ classification). The c.5290_5291del variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 1764 and leads to a premature stop codon 3 codons downstream. This alteration is then predicted to result in a truncated or absent protein and loss of function. Loss of function variants of the BRCA2 gene are an established mechanism of disease in hereditary breast and ovarian cancer and is the type of variant expected to cause the disorder. In summary, based on the above information, this variant meets our laboratoryâ€šÃ„Ã´s criteria to be classified as pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Apr 20, 2024

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