NM_000059.4(BRCA2):c.426-12_426-8del AND Hereditary cancer-predisposing syndrome

Germline classification:: Uncertain significance (3 submissions)
Last evaluated:: Dec 7, 2021
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:: RCV001022168.16

Allele description [Variation Report for NM_000059.4(BRCA2):c.426-12_426-8del]

NM_000059.4(BRCA2):c.426-12_426-8del

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.426-12_426-8del

Other names:

IVS4-12del5

HGVS:

NC_000013.10:g.32900223_32900227delTTTGT
NC_000013.11:g.32326089_32326093del
NG_012772.3:g.15610_15614del
NM_000059.3:c.426-15_426-11delTTTGT
NM_000059.4:c.426-12_426-8delMANE SELECT
LRG_293t1:c.426-12_426-8del
LRG_293:g.15610_15614del
NC_000013.10:g.32900223_32900227del
NC_000013.10:g.32900223_32900227delTTTGT
NC_000013.10:g.32900226_32900230del
NC_000013.10:g.32900226_32900230delGTTTT
NM_000059.3:c.426-12_426-8del
NM_000059.3:c.426-12_426-8del
NM_000059.3:c.426-12_426-8del5
NM_000059.3:c.426-12_426-8delGTTTT
NM_000059.3:c.426-12_426-8delGTTTT
NM_000059.3:c.426-15_426-11delTTTGT
U43746.1:n.654-12_654-8del5

Links:

Breast Cancer Information Core (BIC) (BRCA2): 654-12&base_change=del 5; dbSNP: rs276174844

NCBI 1000 Genomes Browser:

rs276174844

Molecular consequence:

NM_000059.4:c.426-12_426-8del - intron variant - [Sequence Ontology: SO:0001627]

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

Recent activity

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ATP synthase CF0 C subunit (plastid) [Medicago praecox]
ATP synthase CF0 C subunit (plastid) [Medicago praecox]
gi|2091535785|ref|YP_010173277.1|

Protein
protein phosphatase methylesterase-1 [Salvia divinorum]
protein phosphatase methylesterase-1 [Salvia divinorum]
gi|2789766686|gb|KAL1542768.1||gnl| BEAFC|t1.AAHA92_19814

Protein

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001183869	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Uncertain significance (Aug 20, 2020)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 16162645, 19070627, 20215541, 21394826, 24212087, 27060066 Citation Link,
SCV001339313	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (May 27, 2020)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002533861	Sema4, Sema4	criteria provided, single submitter (Sema4 Curation Guidelines)	Uncertain significance (Dec 7, 2021)	germline	curation	PubMed (7) [See all records that cite these PMIDs] 16162645, 19070627, 31980526, 30675319, 18446624, 30883759, 31642931 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001183869

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Uncertain significance
(Aug 20, 2020)

germline

clinical testing

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

Citation Link,

SCV001339313

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(May 27, 2020)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

SCV002533861

Sema4, Sema4

criteria provided, single submitter

(Sema4 Curation Guidelines)

Uncertain significance
(Dec 7, 2021)

germline

curation

PubMed (7)
[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

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

Splicing and multifactorial analysis of intronic BRCA1 and BRCA2 sequence variants identifies clinically significant splicing aberrations up to 12 nucleotides from the intron/exon boundary.

Whiley PJ, Guidugli L, Walker LC, Healey S, Thompson BA, Lakhani SR, Da Silva LM; kConFab Investigators., Tavtigian SV, Goldgar DE, Brown MA, Couch FJ, Spurdle AB.

Hum Mutat. 2011 Jun;32(6):678-87. doi: 10.1002/humu.21495. Epub 2011 Apr 12.

PubMed [citation]

PMID:: 21394826
PMCID:: PMC4340479

See all PubMed Citations (12)

Details of each submission

From Ambry Genetics, SCV001183869.4

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

Description

The c.426-12_426-8delGTTTT intronic variant, results from a deletion of 5 intronic nucleotides upstream of coding exon 4 in the BRCA2 gene. This alteration, designated as IVS4-12del5, was identified in a family with melanoma, breast and pancreatic cancer and segregated with disease in this family. Furthermore, a breast tumor from this family showed loss of heterozygosity for BRCA2 (Zhang L et al. Mutat. Res. 2009 Apr;663:84-9). This variant has been shown to cause incomplete exon skipping, leading to a frameshift and creation of a premature alternative stop codon (Zhang L et al. Mutat. Res. 2009 Apr;663:84-9; Sanz DJ et al. Clin. Cancer Res. 2010 Mar;16:1957-67; Whiley PJ et al. Hum. Mutat. 2011 Jun;32:678-87; Whiley PJ et al. Clin. Chem. 2014 Feb;60:341-52). In addition, internal, quantitative RNA studies have demonstrated this alteration results in a substantial amount of abnormal splicing. However, this alteration has also been reported in trans with other pathogenic BRCA2 variants in patients of unknown age and phenotype who do not have overt symptoms of Fanconi Anemia (Ambry internal data; Nix, P et al. JCO Prec. Onc. 2020 June;4:790-35). Since supporting evidence is conflicting at this time, the clinical significance of this alteration remains unclear.

#	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, SCV001339313.2

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

Description

This variant causes a deletion of 5 nucleotides in intron 4 of the BRCA2 gene. The variant is also known as IVS4-12del5, c.654-12_654-8delGTTTT, and c.426-12_8del5 in the literature. Experimental RNA studies of this variant have demonstrated a partial impact on splicing, increasing the skipping of exon 5 and producing a truncated protein in mutant cells (PMID: 19070627, 20215541, 21394826, 24212087, 30883759, 32133419). However, significant baseline expression of the exon 5 skipped transcript in normal cells may limit the variant's causal impact on disease (PMID: 27060066, 29774201, 32133419). This variant has been reported in individuals affected with breast cancer in the literature, but also in unaffected individuals (PMID: 10923033, 18446624, 19070627, 30675319, 16162645). This variant has also been observed to co-occur with pathogenic variants in BRCA1 (PMID: 18446624, Color Internal data). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Although there is a suspicion for a pathogenic role, the available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

#	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, SCV002533861.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	PubMed (7)

#	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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