NM_000059.4(BRCA2):c.469_470del (p.Lys157fs) AND Hereditary cancer-predisposing syndrome

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Nov 21, 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:: RCV000565817.16

Allele description [Variation Report for NM_000059.4(BRCA2):c.469_470del (p.Lys157fs)]

NM_000059.4(BRCA2):c.469_470del (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.469_470del (p.Lys157fs)

HGVS:

NC_000013.11:g.32326144_32326145del
NG_012772.3:g.15665_15666del
NM_000059.4:c.469_470delMANE SELECT
NP_000050.3:p.Lys157fs
LRG_293:g.15665_15666del
NC_000013.10:g.32900281_32900282del
NC_000013.10:g.32900281_32900282delAA
NM_000059.3:c.469_470delAA
NM_000059.4:c.469_470del
NM_000059.4:c.469_470delAA

Nucleotide change:

697delAA

Links:

dbSNP: rs397507739

NCBI 1000 Genomes Browser:

rs397507739

Molecular consequence:

NM_000059.4:c.469_470del - frameshift variant - [Sequence Ontology: SO:0001589]

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
SCV000673090	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Pathogenic (Nov 21, 2022)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 12491499, 19949876, 20104584, 21553119, 26833046, 27084275 Citation Link,
SCV000683645	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jan 15, 2020)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000673090

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Pathogenic
(Nov 21, 2022)

germline

clinical testing

PubMed (6)
[See all records that cite these PMIDs]

Citation Link,

SCV000683645

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Jan 15, 2020)

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

Citations

PubMed

Pathologic characteristics of breast parenchyma in patients with hereditary breast carcinoma, including BRCA1 and BRCA2 mutation carriers.

Adem C, Reynolds C, Soderberg CL, Slezak JM, McDonnell SK, Sebo TJ, Schaid DJ, Myers JL, Sellers TA, Hartmann LC, Jenkins RB.

Cancer. 2003 Jan 1;97(1):1-11.

PubMed [citation]

PMID:: 12491499

Efficiency of BRCAPRO and Myriad II mutation probability thresholds versus cancer history criteria alone for BRCA1/2 mutation detection.

van Harssel JJ, van Roozendaal CE, Detisch Y, Brandão RD, Paulussen AD, Zeegers M, Blok MJ, Gómez García EB.

Fam Cancer. 2010 Jun;9(2):193-201. doi: 10.1007/s10689-009-9305-1.

PubMed [citation]

PMID:: 19949876
PMCID:: PMC2871096

See all PubMed Citations (7)

Details of each submission

From Ambry Genetics, SCV000673090.6

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

Description

The c.469_470delAA pathogenic mutation, located in coding exon 4 of the BRCA2 gene, results from a deletion of two nucleotides at nucleotide positions 469 to 470, causing a translational frameshift with a predicted alternate stop codon (p.K157Vfs*25). This alteration has been reported in multiple individuals and families with a history of breast, ovarian, and/or prostate cancer (Borg A et al. Hum. Mutat. 2010 Mar; 31(3):E1200-40. Adem C et al. Cancer 2003 Jan; 97(1):1-11; van Harssel JJ et al. Fam. Cancer 2010 Jun; 9(2):193-201; Nielsen HR et al. Fam. Cancer 2016 Feb; Hart SN et al. BMJ Open 2016; 6(4):e010332). Of note, this alteration is also designated as 697delAA in the 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, SCV000683645.3

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

Description

This variant deletes 2 nucleotides in exon 5 of the BRCA2 gene, 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 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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