NM_000059.4(BRCA2):c.5722_5723del (p.Leu1908fs) AND Hereditary cancer-predisposing syndrome

Germline classification:: Pathogenic (3 submissions)
Last evaluated:: Apr 4, 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:: RCV000131120.21

Allele description [Variation Report for NM_000059.4(BRCA2):c.5722_5723del (p.Leu1908fs)]

NM_000059.4(BRCA2):c.5722_5723del (p.Leu1908fs)

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.5722_5723del (p.Leu1908fs)

Other names:

5946delCT; 5950_5951delCT; p.Leu1908ArgfsTer2

HGVS:

NC_000013.10:g.32914210_32914211del
NC_000013.11:g.32340073CT[2]
NG_012772.3:g.29594CT[2]
NG_012772.3:g.29598_29599del
NM_000059.4:c.5722_5723delMANE SELECT
NP_000050.3:p.Leu1908fs
LRG_293:g.29594CT[2]
NC_000013.10:g.32914210CT[2]
NC_000013.10:g.32914210_32914211del
NC_000013.10:g.32914214_32914215delCT
NC_000013.11:g.32340077_32340078delCT
NG_012772.3:g.29598_29599del
NM_000059.3:c.5718_5719del
NM_000059.3:c.5722_5723delCT
NM_000059.4:c.5722_5723delCT
U43746.1:n.5950_5951delCT
p.L1908RFS*2
p.L1908RfsX2
p.Leu1908Argfs*2
p.Leu1908ArgfsX2

Nucleotide change:

5950delCT

Protein change:

L1908fs

Links:

Breast Cancer Information Core (BIC) (BRCA2): 5946&base_change=del CT; Breast Cancer Information Core (BIC) (BRCA2): 5950&base_change=del CT; OMIM: 600185.0004; dbSNP: rs80359530

NCBI 1000 Genomes Browser:

rs80359530

Molecular consequence:

NM_000059.4:c.5722_5723del - frameshift variant - [Sequence Ontology: SO:0001589]

Functional consequence:

loss_of_function_variant [Sequence Ontology: SO:0002054]

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

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000186050	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Pathogenic (Feb 21, 2022)	germline	clinical testing	PubMed (22) [See all records that cite these PMIDs] 20683152, 20736950, 20927582, 21324516, 23028338, 24010542, 24963353, 25136594, 25863477, 25940717, 26026974, 27553291, 27989354, 28724667, 29470806, 30720863, 30940775, 31577767, 31742824, 32341426, 34290354, 8524414 Citation Link,
SCV000683728	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Apr 4, 2023)	germline	clinical testing	PubMed (23) [See all records that cite these PMIDs] 8524414, 8665505, 11802209, 14647210, 15340362, 16234499, 19353265, 20683152, 20736950, 21324516, 24010542, 24963353, 25136594, 25863477, 25940717, 26026974, 27553291, 28724667, 29470806, 30287823, 31214711, 33471991, 25741868
SCV002536167	Sema4, Sema4	criteria provided, single submitter (Sema4 Curation Guidelines)	Pathogenic (Feb 16, 2022)	germline	curation	PubMed (8) [See all records that cite these PMIDs] 33471991, 23028338, 20927582, 21324516, 34026625, 27989354, 25940717, 29446198 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000186050

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Pathogenic
(Feb 21, 2022)

germline

clinical testing

PubMed (22)
[See all records that cite these PMIDs]

Citation Link,

SCV000683728

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Apr 4, 2023)

germline

clinical testing

PubMed (23)
[See all records that cite these PMIDs]

SCV002536167

Sema4, Sema4

criteria provided, single submitter

(Sema4 Curation Guidelines)

Pathogenic
(Feb 16, 2022)

germline

curation

PubMed (8)
[See all records that cite these PMIDs]

Citation Link

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, curation

Citations

PubMed

Prevalence and clinical outcomes of germline mutations in BRCA1/2 and PALB2 genes in 2769 unselected breast cancer patients in China.

Deng M, Chen HH, Zhu X, Luo M, Zhang K, Xu CJ, Hu KM, Cheng P, Zhou JJ, Zheng S, Chen YD.

Int J Cancer. 2019 Sep 15;145(6):1517-1528. doi: 10.1002/ijc.32184. Epub 2019 Feb 22.

PubMed [citation]

PMID:: 30720863

Identifying a BRCA2 c.5722_5723del mutation in a Han-Chinese family with breast cancer.

Guo Y, Wang P, Li X, Zhu S, Xu H, Li S, Deng H, Yuan L.

Biosci Rep. 2019 Apr 30;39(4). doi:pii: BSR20182471. 10.1042/BSR20182471. Print 2019 Apr 30.

PubMed [citation]

PMID:: 30940775
PMCID:: PMC6488854

See all PubMed Citations (34)

Details of each submission

From Ambry Genetics, SCV000186050.8

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (22)

Description

The c.5722_5723delCT pathogenic mutation, located in coding exon 10 of the BRCA2 gene, results from a deletion of two nucleotides at nucleotide positions 5722 to 5723, causing a translational frameshift with a predicted alternate stop codon (p.L1908Rfs*2). This mutation has been reported in multiple hereditary breast and ovarian cancer (HBOC) syndrome cohorts, including individuals with male breast cancer, pancreatic cancer and prostate cancer (Wooster R et al. Nature. 1995 Dec;378:789-92; Edwards SM et al. Br. J. Cancer. 2010 Sep;103:918-24; Cherbal F et al. Dis Markers, 2010;28:377-84; Ding YC et al. Breast Cancer Res. Treat. 2011 Apr;126:771-8; Zhang S et al. Gynecol. Oncol. 2011 May;121(2):353-7; Konstantopoulou I et al. Clin. Genet. 2014 Jan;85:36-42; Johns AL et al. Genome Med. 2014 May;6:42; Ruiz A et al. Biomed Res Int. 2014 Jun;2014:542541; Kang E et al. Breast Cancer Res. Treat. 2015 May;151:157-68; Holter S et al. J. Clin. Oncol. 2015 Oct;33:3124-9; de Juan I et al. Fam. Cancer. 2015 Dec;14:505-13; Rashid MU et al. BMC Cancer. 2016 08;16:673; Na R et al. Eur Urol, 2017 05;71:740-747; Sun J et al. Clin. Cancer Res. 2017 Oct;23:6113-6119; Singh J et al. Breast Cancer Res Treat, 2018 Jul;170:189-196; Momozowa Y et al. Nat Commun. 2018 10;9(1):4083; Wang H et al. Medicine (Baltimore), 2019 Oct;98:e17443; Guo Y et al. Biosci Rep, 2019 04;39; Deng M et al. Int J Cancer, 2019 09;145:1517-1528; De Talhouet S et al. Sci Rep, 2020 04;10:7073; Shao D et al. Cancer Sci, 2020 Feb;111:647-657; Abdel-Razeq H et al. Sci Rep, 2021 07;11:14906). Of note, this mutation is also designated as 5950delCT and c.5718_5719del 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, SCV000683728.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (23)

Description

This variant deletes 2 nucleotides in exon 11 of the BRCA2 gene, creating a frameshift and premature translation stop signal. This variant is also known as 5950delCT, 5946delCT and 5950-5951delCT in the literature. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in at least 12 individuals affected with breast and/or ovarian cancer (PMID: 8665505, 14647210, 19353265, 20683152, 21324516, 24010542, 25136594, 26026974, 27553291, 28724667, 29470806, 30287823, 33471991; Leiden Open Variation Database DB-ID BRCA2_001607) and five individuals affected with pancreatic cancer (PMID: 24963353, 25940717) or prostate cancer (PMID: 20736950, 31214711). This variant also has been reported in families suspected of being affected with hereditary breast and ovarian cancer (PMID: 8524414, 11802209, 15340362, 16234499, 25863477). This variant has been identified in 1/250888 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

From Sema4, Sema4, SCV002536167.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	PubMed (8)

#	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: Nov 3, 2024

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