NM_000059.4(BRCA2):c.9117G>A (p.Pro3039=) AND Hereditary cancer-predisposing syndrome

Germline classification:: Pathogenic (3 submissions)
Last evaluated:: Apr 19, 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:: RCV000131039.19

Allele description [Variation Report for NM_000059.4(BRCA2):c.9117G>A (p.Pro3039=)]

NM_000059.4(BRCA2):c.9117G>A (p.Pro3039=)

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.9117G>A (p.Pro3039=)

Other names:

P3039P; p.P3039P:CCG>CCA; NM_000059.4(BRCA2):c.9117G>A; p.Pro3039=

HGVS:

NC_000013.11:g.32379913G>A
NG_012772.3:g.69434G>A
NM_000059.4:c.9117G>AMANE SELECT
NP_000050.2:p.Pro3039=
NP_000050.3:p.Pro3039=
LRG_293t1:c.9117G>A
LRG_293:g.69434G>A
LRG_293p1:p.Pro3039=
NC_000013.10:g.32954050G>A
NM_000059.3:c.9117G>A
U43746.1:n.9345G>A
p.P3039P

Nucleotide change:

9345G>A

Links:

dbSNP: rs28897756

NCBI 1000 Genomes Browser:

rs28897756

Molecular consequence:

NM_000059.4:c.9117G>A - synonymous variant - [Sequence Ontology: SO:0001819]

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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amplicon.MF03.CALR
amplicon.MF03.CALR

biosample
SAMN11533753 (1)
SRA
10x.ET05
10x.ET05

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000185969	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Pathogenic (Apr 8, 2022)	germline	clinical testing	PubMed (30) [See all records that cite these PMIDs] 10638982, 11897832, 16683254, 17011978, 17148771, 17924331, 18375895, 18821011, 19016756, 19656164, 20406929, 21324516, 21990134, 22217648, 22505045, 22632462, 22798144, 22923021, 23035815, 24156927, 24249303, 25382762, 25480878, 25556971, 25948282, 26026974, 27000661, 27271530, 28477318, 28724667 Citation Link,
SCV000537643	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Apr 19, 2023)	germline	clinical testing	PubMed (19) [See all records that cite these PMIDs] 18821011, 22505045, 22798144, 23451180, 24156927, 24249303, 25382762, 25480878, 25556971, 25948282, 26026974, 27000661, 27060066, 28477318, 28724667, 30287823, 31843900, 32393398, 25741868
SCV002532009	Sema4, Sema4	criteria provided, single submitter (Sema4 Curation Guidelines)	Pathogenic (Jul 1, 2021)	germline	curation	PubMed (10) [See all records that cite these PMIDs] 25186627, 28477318, 28724667, 28825054, 29176636, 32393398, 10638982, 17011978, 23451180, 29446198 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000185969

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Pathogenic
(Apr 8, 2022)

germline

clinical testing

PubMed (30)
[See all records that cite these PMIDs]

Citation Link,

SCV000537643

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Apr 19, 2023)

germline

clinical testing

PubMed (19)
[See all records that cite these PMIDs]

SCV002532009

Sema4, Sema4

criteria provided, single submitter

(Sema4 Curation Guidelines)

Pathogenic
(Jul 1, 2021)

germline

curation

PubMed (10)
[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

Contribution of BRCA2 germline mutations to hereditary breast/ovarian cancer in Germany.

Hamann U, Liu X, Lange S, Ulmer HU, Benner A, Scott RJ.

J Med Genet. 2002 Mar;39(3):E12. No abstract available.

PubMed [citation]

PMID:: 11897832
PMCID:: PMC1735066

A DGGE system for comprehensive mutation screening of BRCA1 and BRCA2: application in a Dutch cancer clinic setting.

van der Hout AH, van den Ouweland AM, van der Luijt RB, Gille HJ, Bodmer D, Brüggenwirth H, Mulder IM, van der Vlies P, Elfferich P, Huisman MT, ten Berge AM, Kromosoeto J, Jansen RP, van Zon PH, Vriesman T, Arts N, Lange MB, Oosterwijk JC, Meijers-Heijboer H, Ausems MG, Hoogerbrugge N, Verhoef S, et al.

Hum Mutat. 2006 Jul;27(7):654-66.

PubMed [citation]

PMID:: 16683254

See all PubMed Citations (40)

Details of each submission

From Ambry Genetics, SCV000185969.8

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (30)

Description

The c.9117G>A pathogenic mutation (also known as p.P3039P), located in coding exon 22 of the BRCA2 gene, results from a G to A substitution at nucleotide position 9117. This nucleotide substitution does not change the at codon 3039. However, this change occurs in the last base pair of coding exon 22 and has been shown to cause aberrant RNA transcripts due to exon skipping that results in a frameshift at codon 2985 and premature protein truncation (V2985Gfs*3) (Ambry internal data; Houdayer C et al. Hum. Mutat. 2012 Aug;33:1228-38; Acedo A et al. Hum. Mutat. 2015 Feb;36:210-21). This alteration has been reported in multiple families with hereditary breast and/or ovarian cancer (Hamann U et al. J. Med. Genet. 2002 Mar;39:E12; Spurdle AB et al. J. Clin. Oncol. 2008 Apr;26:1657-63; Fong PC et al. J. Clin. Oncol. 2010 May;28:2512-9; Novakovi S et al. Int. J. Oncol. 2012 Nov;41:1619-27; Takahashi M et al. Breast Cancer. 2017 Mar;24(2):336-340; Heramb C et al. Hered Cancer Clin Pract 2018 Jan;16:3; Arai M et al. J. Hum. Genet. 2018 Apr;63(4):447-457). This alteration has also been reported in a male with aggressive prostate cancer (Willems-Jones A et al. BJU Int. 2012 Dec;110:E1181-6) and in biological males with breast cancer (de Juan I et al. Fam. Cancer. 2015 Dec;14:505-13; Corman V et al. Endocr. Relat. Cancer. 2016 May;23:391-7). Of note, this mutation is also designated as 9345G>A in published literature. Based on the supporting evidence, 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, SCV000537643.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (19)

Description

This variant changes a conserved and the last nucleotide in exon 23, and it is predicted to disrupt the intron 23 splice donor site. RNA studies have shown that this variant impacts splicing resulting in exon 23 skipping and introducing premature stop (PMID: 22505045, 23451180, 25382762, 27060066, 31843900, 32393398). This variant is expected to result in an absent or non-functional protein product. This variant has been reported in at least 10 individuals affected with breast or ovarian cancer (PMID: 18821011, 22798144, 24156927, 24249303, 25480878, 25556971, 25948282, 26026974, 27000661, 28477318, 28724667, 30287823). This variant has been identified in 1/248378 chromosomes 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 Sema4, Sema4, SCV002532009.1

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

#	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 3, 2024

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