NM_000059.4(BRCA2):c.470_474del (p.Lys157fs) AND Hereditary cancer-predisposing syndrome

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Mar 8, 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:: RCV000131856.16

Allele description [Variation Report for NM_000059.4(BRCA2):c.470_474del (p.Lys157fs)]

NM_000059.4(BRCA2):c.470_474del (p.Lys157fs)

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.470_474del (p.Lys157fs)

Other names:

698_702delAGTCA

HGVS:

NC_000013.10:g.32900281_32900285del
NC_000013.11:g.32326145_32326149del
NG_012772.3:g.15666_15670del
NM_000059.4:c.470_474delMANE SELECT
NM_000059.4:c.470_474delAGTCA
NP_000050.3:p.Lys157fs
LRG_293:g.15666_15670del
NC_000013.10:g.32900281_32900285del
NC_000013.10:g.32900282_32900286del
NC_000013.10:g.32900282_32900286delAGTCA
NM_000059.3:c.470_474delAGTCA
NM_000059.4:c.470_474del
U43746.1:n.698_702delAGTCA
p.K157Sfs*24
p.Lys157Serfs*24

Nucleotide change:

698del5

Links:

Breast Cancer Information Core (BIC) (BRCA2): 698&base_change=del AGTCA; dbSNP: rs80359463

NCBI 1000 Genomes Browser:

rs80359463

Molecular consequence:

NM_000059.4:c.470_474del - frameshift variant - [Sequence Ontology: SO:0001589]

Observations:

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
SCV000186911	Ambry Genetics	criteria provided, single submitter (Ambry Autosomal Dominant and X-Linked criteria (10/2015))	Pathogenic (May 4, 2015)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 17851763, 20215541 Citation Link,
SCV000683646	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 8, 2022)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 17851763, 28294317, 29446198, 29487695, 31174498, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000186911

Ambry Genetics

criteria provided, single submitter

(Ambry Autosomal Dominant and X-Linked criteria (10/2015))

Pathogenic
(May 4, 2015)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

Citation Link,

SCV000683646

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Mar 8, 2022)

germline

clinical testing

PubMed (6)
[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	unknown	1	not provided	not provided	1	not provided	clinical testing

Citations

PubMed

A high proportion of DNA variants of BRCA1 and BRCA2 is associated with aberrant splicing in breast/ovarian cancer patients.

Sanz DJ, Acedo A, Infante M, Durán M, Pérez-Cabornero L, Esteban-Cardeñosa E, Lastra E, Pagani F, Miner C, Velasco EA.

Clin Cancer Res. 2010 Mar 15;16(6):1957-67. doi: 10.1158/1078-0432.CCR-09-2564. Epub 2010 Mar 9.

PubMed [citation]

PMID:: 20215541

The prevalence of BRCA1 and BRCA2 germline mutations in high-risk breast cancer patients of Chinese Han nationality: two recurrent mutations were identified.

Li WF, Hu Z, Rao NY, Song CG, Zhang B, Cao MZ, Su FX, Wang YS, He PQ, Di GH, Shen KW, Wu J, Lu JS, Luo JM, Liu XY, Zhou J, Wang L, Zhao L, Liu YB, Yuan WT, Yang L, Shen ZZ, et al.

Breast Cancer Res Treat. 2008 Jul;110(1):99-109. Epub 2007 Sep 13.

PubMed [citation]

PMID:: 17851763

See all PubMed Citations (7)

Details of each submission

From Ambry Genetics, SCV000186911.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (2)

Description

Ã¢â‚¬â€¹The c.470_474delAGTCA (also known as 698del5, c.470del5, and p.K157Sfs*24) pathogenic mutation located in coding exon 4 of the BRCA2 gene, results from a deletion of 5 nucleotides between nucleotide positions 470 and 474, causing a translational frameshift with a predicted alternate stop codon. In addition to causing premature protein truncation, functional splicing analysis demonstrates that this alteration also results in exon 5 skipping via disruption of the exonic splicing enhancer (Sanz DJ et al. Clin. Cancer Res. 2010; 16:1957-67). This alteration was previously reported in one individual with breast cancer at age 32 from a Chinese cohort of 489 breast cancer patients with a diagnosis under the age of 35 or a family history of breast and/or ovarian cancer ( Li WF et al. Breast Cancer Res. Treat. 2008; 110:99-109). In addition to the clinical data presented in the literature, since frameshifts are typically deleterious in nature, this alteration is interpreted as a disease-causing mutation (ACMG Recommendations for Standards for Interpretation and Reporting of Sequence Variations. Revision 2007. Genet Med. 2008;10:294).

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

From Color Diagnostics, LLC DBA Color Health, SCV000683646.3

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

Description

This variant deletes 5 nucleotides in exon 5 of the BRCA2 protein, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in 11 individuals affected with breast or ovarian cancer (PMID: 17851763, 28294317, 29487695, 31174498, doi:10.1515/tjb-2019-0424) and has been identified in 5 families among the CIMBA participants (PMID: 29446198). This variant has not been identified 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

Last Updated: Nov 10, 2024

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