NM_000059.4(BRCA2):c.5585_5588del (p.Val1862fs) AND not provided

Germline classification:: Pathogenic (4 submissions)
Last evaluated:: Dec 6, 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:: RCV000223488.22

Allele description [Variation Report for NM_000059.4(BRCA2):c.5585_5588del (p.Val1862fs)]

NM_000059.4(BRCA2):c.5585_5588del (p.Val1862fs)

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.5585_5588del (p.Val1862fs)

HGVS:

NC_000013.11:g.32339940_32339943del
NG_012772.3:g.29461_29464del
NM_000059.4:c.5585_5588delMANE SELECT
NP_000050.3:p.Val1862fs
LRG_293:g.29461_29464del
NC_000013.10:g.32914077_32914080del
NC_000013.10:g.32914077_32914080delTGAA
NM_000059.3:c.5585_5588delTGAA
NM_000059.4:c.5585_5588del
U43746.1:n.5813_5816delTGAA
p.V1862Efs*11
p.Val1862fs

Nucleotide change:

5813del4

Links:

Breast Cancer Information Core (BIC) (BRCA2): 5813&base_change=del TGAA; dbSNP: rs80359523

NCBI 1000 Genomes Browser:

rs80359523

Molecular consequence:

NM_000059.4:c.5585_5588del - frameshift variant - [Sequence Ontology: SO:0001589]

Condition(s)

Synonyms:: none provided; RECLASSIFIED - ADRA2C POLYMORPHISM; RECLASSIFIED - ADRB1 POLYMORPHISM
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000278861	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (May 7, 2024)	germline	clinical testing	Citation Link,
SCV000885098	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process)	Pathogenic (Mar 13, 2018)	germline	clinical testing	Citation Link,
SCV001470432	Quest Diagnostics Nichols Institute San Juan Capistrano	criteria provided, single submitter (Quest Diagnostics criteria)	pathogenic (Dec 6, 2024)	unknown	clinical testing	PubMed (6) [See all records that cite these PMIDs] 37461096, 32614418, 27433846, 25186627, 29446198, 26467025
SCV004238739	Revvity Omics, Revvity	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 2, 2023)	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	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
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Landscape of germline pathogenic variants in patients with dual primary breast and lung cancer.

Lee NY, Hum M, Zihara S, Wang L, Myint MK, Lim DW, Toh CK, Skanderup A, Samol J, Tan MH, Ang P, Lee SC, Tan EH, Lai GGY, Tan DSW, Yap YS, Lee ASG.

Hum Genomics. 2023 Jul 17;17(1):66. doi: 10.1186/s40246-023-00510-7. Erratum in: Hum Genomics. 2023 Aug 14;17(1):74. doi: 10.1186/s40246-023-00518-z..

PubMed [citation]

PMID:: 37461096
PMCID:: PMC10353088

Characterization of the Cancer Spectrum in Men With Germline BRCA1 and BRCA2 Pathogenic Variants: Results From the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA).

Silvestri V, Leslie G, Barnes DR; CIMBA Group, Agnarsson BA, Aittomäki K, Alducci E, Andrulis IL, Barkardottir RB, Barroso A, Barrowdale D, Benitez J, Bonanni B, Borg A, Buys SS, Caldés T, Caligo MA, Capalbo C, Campbell I, Chung WK, Claes KBM, Colonna SV, et al.

JAMA Oncol. 2020 Aug 1;6(8):1218-1230. doi: 10.1001/jamaoncol.2020.2134. Erratum in: JAMA Oncol. 2020 Nov 1;6(11):1815. doi: 10.1001/jamaoncol.2020.4696..

PubMed [citation]

PMID:: 32614418
PMCID:: PMC7333177

See all PubMed Citations (7)

Details of each submission

From GeneDx, SCV000278861.11

#	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; Observed in individuals with BRCA2-related cancers (PMID: 27433846, 25186627); Not observed at significant frequency in large population cohorts (gnomAD); Also known as 5813_5816delTGAA or 5813del4; Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; This variant is associated with the following publications: (PMID: 27433846, 25186627, 29446198, 31853058)

#	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 ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories, SCV000885098.1

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

Description

The BRCA2 c.5585_5588del; p.Val1862fs variant (rs80359523) has been described in individuals affected with breast and prostate cancer (Pritchard 2016, Tung 2015). It is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 51885) and is absent from general population databases (1000 Genomes Project, Exome Variant Server, and Genome Aggregation Database), indicating it is not a common polymorphism. This variant causes a frameshift by deleting 4 nucleotides, so is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered pathogenic. REFERENCES Pritchard C et al. Inherited DNA-Repair Gene Mutations in Men with Metastatic Prostate Cancer. N Engl J Med. 2016 Aug 4;375(5):443-53. Tung N et al. Frequency of mutations in individuals with breast cancer referred for BRCA1 and BRCA2 testing using next-generation sequencing with a 25-gene panel. Cancer. 2015 Jan 1;121(1):25-33.

#	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 Quest Diagnostics Nichols Institute San Juan Capistrano, SCV001470432.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

The BRCA2 c.5585_5588del (p.Val1862Glufs*11) variant alters the translational reading frame of the BRCA2 mRNA and causes the premature termination of BRCA2 protein synthesis. This variant has been reported in the published literature in individuals with breast cancer (PMID: 25186627 (2015)) and prostate cancer (PMID: 27433846 (2016)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). 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 Revvity Omics, Revvity, SCV004238739.1

#	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

Last Updated: May 16, 2025

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