NM_000059.4(BRCA2):c.9774_9775del (p.Glu3258fs) AND Hereditary breast ovarian cancer syndrome

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Feb 9, 2023
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV002851230.3

Allele description [Variation Report for NM_000059.4(BRCA2):c.9774_9775del (p.Glu3258fs)]

NM_000059.4(BRCA2):c.9774_9775del (p.Glu3258fs)

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.9774_9775del (p.Glu3258fs)

HGVS:

NC_000013.11:g.32398285GA[1]
NG_012772.3:g.87806GA[1]
NM_000059.4:c.9774_9775delMANE SELECT
NM_001406719.1:c.9676_9677GA[1]
NM_001406720.1:c.9721_9722GA[1]
NM_001406721.1:c.4840_4841GA[1]
NM_001406722.1:c.3355_3356GA[1]
NP_000050.2:p.Glu3258Aspfs
NP_000050.3:p.Glu3258fs
NP_001393648.1:p.Glu3226Aspfs
NP_001393649.1:p.Glu3241Aspfs
NP_001393650.1:p.Glu1614Aspfs
NP_001393651.1:p.Glu1119Aspfs
LRG_293t1:c.9772_9773GA[1]
LRG_293:g.87806GA[1]
LRG_293p1:p.Glu3258Aspfs
NC_000013.10:g.32972421_32972422del
NC_000013.10:g.32972422GA[1]
NM_000059.3:c.9772_9773GA[1]
NR_176251.1:n.10035_10036GA[1]

Protein change:

E3258fs

Molecular consequence:

NM_000059.4:c.9774_9775del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001406719.1:c.9676_9677GA[1] - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001406720.1:c.9721_9722GA[1] - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001406721.1:c.4840_4841GA[1] - frameshift variant - [Sequence Ontology: SO:0001589]
NM_001406722.1:c.3355_3356GA[1] - frameshift variant - [Sequence Ontology: SO:0001589]

Condition(s)

Name:: Hereditary breast ovarian cancer syndrome
Synonyms:: Hereditary breast and ovarian cancer syndrome; Hereditary breast and ovarian cancer; Hereditary breast and ovarian cancer syndrome (HBOC); See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0003582; MeSH: D061325; MedGen: C0677776; Orphanet: 145

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV003217959	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Feb 9, 2023)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 17026620, 18593900, 18607349, 22711857, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV003217959

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Feb 9, 2023)

germline

clinical testing

PubMed (5)
[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	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Inherited association of breast and colorectal cancer: limited role of CHEK2 compared with high-penetrance genes.

Naseem H, Boylan J, Speake D, Leask K, Shenton A, Lalloo F, Hill J, Trump D, Evans DG.

Clin Genet. 2006 Nov;70(5):388-95.

PubMed [citation]

PMID:: 17026620

A syngeneic variance library for functional annotation of human variation: application to BRCA2.

Hucl T, Rago C, Gallmeier E, Brody JR, Gorospe M, Kern SE.

Cancer Res. 2008 Jul 1;68(13):5023-30. doi: 10.1158/0008-5472.CAN-07-6189.

PubMed [citation]

PMID:: 18593900
PMCID:: PMC2536704

See all PubMed Citations (5)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV003217959.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

This sequence change creates a premature translational stop signal (p.Glu3258Aspfs*2) in the BRCA2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 161 amino acid(s) of the BRCA2 protein. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with BRCA2-related conditions. This variant disrupts a region of the BRCA2 protein in which other variant(s) (p.Tyr3308*) have been determined to be pathogenic (PMID: 17026620, 18593900, 18607349, 22711857). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been 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: Sep 29, 2024

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