NM_000059.4(BRCA2):c.67+1G>T AND Hereditary cancer-predisposing syndrome

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Mar 4, 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:: RCV000162894.15

Allele description [Variation Report for NM_000059.4(BRCA2):c.67+1G>T]

NM_000059.4(BRCA2):c.67+1G>T

Gene:

BRCA2:BRCA2 DNA repair associated [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

13q13.1

Genomic location:

Preferred name:

NM_000059.4(BRCA2):c.67+1G>T

HGVS:

NC_000013.11:g.32316528G>T
NG_012772.3:g.6049G>T
NG_017006.2:g.3836C>A
NM_000059.4:c.67+1G>TMANE SELECT
NM_001406719.1:c.67+1G>T
NM_001406720.1:c.67+1G>T
NM_001406721.1:c.67+1G>T
NM_001406722.1:c.-303+861G>T
LRG_293t1:c.67+1G>T
LRG_293:g.6049G>T
NC_000013.10:g.32890665G>T
NM_000059.3:c.67+1G>T
U43746.1:n.295+1G>T

Nucleotide change:

IVS2+1G>T

Links:

Breast Cancer Information Core (BIC) (BRCA2): 295+1&base_change=G to T; dbSNP: rs81002796

NCBI 1000 Genomes Browser:

rs81002796

Molecular consequence:

NM_001406722.1:c.-303+861G>T - intron variant - [Sequence Ontology: SO:0001627]
NM_000059.4:c.67+1G>T - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001406719.1:c.67+1G>T - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001406720.1:c.67+1G>T - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001406721.1:c.67+1G>T - splice donor variant - [Sequence Ontology: SO:0001575]

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
SCV000213381	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Pathogenic (Dec 27, 2021)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 12938098, 22505045, 24302565, 28185119, 29446198, 30883759 Citation Link,
SCV000904689	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 4, 2022)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 25342642, 31706072, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000213381

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Pathogenic
(Dec 27, 2021)

germline

clinical testing

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

Citation Link,

SCV000904689

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Mar 4, 2022)

germline

clinical testing

PubMed (3)
[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

Twenty-three novel BRCA1 and BRCA2 sequence alterations in breast and/or ovarian cancer families in Southern Germany.

Meyer P, Voigtlaender T, Bartram CR, Klaes R.

Hum Mutat. 2003 Sep;22(3):259.

PubMed [citation]

PMID:: 12938098

Guidelines for splicing analysis in molecular diagnosis derived from a set of 327 combined in silico/in vitro studies on BRCA1 and BRCA2 variants.

Houdayer C, Caux-Moncoutier V, Krieger S, Barrois M, Bonnet F, Bourdon V, Bronner M, Buisson M, Coulet F, Gaildrat P, Lefol C, Léone M, Mazoyer S, Muller D, Remenieras A, Révillion F, Rouleau E, Sokolowska J, Vert JP, Lidereau R, Soubrier F, Sobol H, et al.

Hum Mutat. 2012 Aug;33(8):1228-38. doi: 10.1002/humu.22101. Epub 2012 May 11.

PubMed [citation]

PMID:: 22505045

See all PubMed Citations (9)

Details of each submission

From Ambry Genetics, SCV000213381.7

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

Description

The c.67+1G>T intronic variant results from a G to T substitution one nucleotide after exon 2 (coding exon 1) of the BRCA2 gene. Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This mutation has been reported in multiple German individuals with breast and/or ovarian cancer (Meyer, 2003; Rebbeck, 2018). This nucleotide position is highly conserved in available vertebrate species. This alteration, as well as several close match alterations at this donor site have been shown by multiple assays to result in skipping of exon 2 (coding exon 1) with resulting predicted loss of the translational start codon (Houdayer, 2012; Parsons, 2015; Feben, 2017; Fraile-Bethencourt, 2019; Ambry internal data). In silico splice site analysis predicts that this alteration will weaken the native splice donor site. Based on the available evidence, this alteration 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 Color Diagnostics, LLC DBA Color Health, SCV000904689.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

This variant causes a G to T nucleotide substitution at the +1 position of intron 2 of the BRCA2 gene. Functional RNA studies have shown that this variant causes skipping of exon 2, expected to result in the loss of the initiator methionine. This variant has been reported in individuals affected with breast and ovarian cancer (PMID: 25342642, 31706072, doi.org/10.1515/tjb-2019-0424). 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: Jun 2, 2024

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