NM_000059.4(BRCA2):c.7617+1G>A AND Hereditary cancer-predisposing syndrome

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Apr 4, 2023
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:: RCV000579436.15

Allele description [Variation Report for NM_000059.4(BRCA2):c.7617+1G>A]

NM_000059.4(BRCA2):c.7617+1G>A

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.7617+1G>A

HGVS:

NC_000013.11:g.32356610G>A
NG_012772.3:g.46131G>A
NM_000059.4:c.7617+1G>AMANE SELECT
NM_001406719.1:c.7521+1G>A
NM_001406720.1:c.7617+1G>A
NM_001406721.1:c.2685+1G>A
NM_001406722.1:c.1200+1G>A
LRG_293t1:c.7617+1G>A
LRG_293:g.46131G>A
NC_000013.10:g.32930747G>A
NM_000059.3:c.7617+1G>A

Nucleotide change:

IVS15+1G>A

Links:

dbSNP: rs397507922

NCBI 1000 Genomes Browser:

rs397507922

Molecular consequence:

NM_000059.4:c.7617+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001406719.1:c.7521+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001406720.1:c.7617+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001406721.1:c.2685+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001406722.1:c.1200+1G>A - 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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arginine N-methyltransferase 1 [Schistosoma japonicum]
arginine N-methyltransferase 1 [Schistosoma japonicum]
gi|224813804|gb|ACN65119.1|

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000683893	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Apr 4, 2023)	germline	clinical testing	PubMed (11) [See all records that cite these PMIDs] 11389159, 12097290, 17301269, 20927582, 21184276, 24123850, 26187060, 26360800, 26833046, 31191615, 25741868
SCV001189045	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Pathogenic (Sep 29, 2022)	germline	clinical testing	PubMed (10) [See all records that cite these PMIDs] 11389159, 18712473, 21184276, 23479189, 24123850, 25525159, 26360800, 26833046, 30720863, 31191615 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000683893

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Apr 4, 2023)

germline

clinical testing

PubMed (11)
[See all records that cite these PMIDs]

SCV001189045

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Pathogenic
(Sep 29, 2022)

germline

clinical testing

PubMed (10)
[See all records that cite these PMIDs]

Citation Link

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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

Evaluation of candidate genes MAP2K4, MADH4, ACVR1B, and BRCA2 in familial pancreatic cancer: deleterious BRCA2 mutations in 17%.

Murphy KM, Brune KA, Griffin C, Sollenberger JE, Petersen GM, Bansal R, Hruban RH, Kern SE.

Cancer Res. 2002 Jul 1;62(13):3789-93.

PubMed [citation]

PMID:: 12097290

The prevalence of BRCA2 mutations in familial pancreatic cancer.

Couch FJ, Johnson MR, Rabe KG, Brune K, de Andrade M, Goggins M, Rothenmund H, Gallinger S, Klein A, Petersen GM, Hruban RH.

Cancer Epidemiol Biomarkers Prev. 2007 Feb;16(2):342-6.

PubMed [citation]

PMID:: 17301269

See all PubMed Citations (15)

Details of each submission

From Color Diagnostics, LLC DBA Color Health, SCV000683893.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (11)

Description

This variant causes a G to A nucleotide substitution at the +1 position of intron 15 of the BRCA2 gene. RNA studies have shown that this variant causes skipping of exon 15, resulting in premature truncation (PMID: 11389159, 21184276, 24123850, 31191615). This variant has been reported in individuals affected with breast/ovarian cancer (PMID: 11389159, 20927582, 21184276, 24123850, 26187060, 26360800, 26833046) or pancreatic cancer (PMID: 12097290, 17301269). 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

From Ambry Genetics, SCV001189045.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (10)

Description

The c.7617+1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide after coding exon 14 of the BRCA2 gene. This nucleotide position is highly conserved in available vertebrate species. This alteration has been described as a Danish founder pathogenic mutation and it segregates strongly with disease in many Danish families (Thomassen M et al. Breast Cancer Res. Treat., 2011 Jul;128:179-85; de Juan Jiménez I et al. Fam. Cancer, 2013 Dec;12:767-77; Roed Nielsen H et al. Acta Oncol, 2016 Sep;55:38-44; Nielsen HR et al. Fam. Cancer, 2016 Oct;15:507-12 ). In silico splice site analysis predicts that this alteration will weaken the native splice donor site. RNA analyses using patient RNA and minigene assays have shown this alteration results in complete loss of exon 15 (Ambry internal data; Bergthorsson JT et al. J. Med. Genet., 2001 Jun;38:361-8; Gutiérrez-Enríquez S et al. Breast Cancer Res. Treat., 2009 Sep;117:461-5; Thomassen M et al. Breast Cancer Res. Treat., 2011 Jul;128:179-85; Fraile-Bethencourt E et al. Front Genet, 2019 May;10:503; de Garibay GR et al. Hum Mutat, 2014 Jan;35:53-7). Of note, this alteration is also designated as IVS15+1G>A and 7845+1G>A in published literature. In addition to the clinical data presented in the literature, 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. As such, this alteration is classified 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

Last Updated: Oct 20, 2024

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