NM_000059.4(BRCA2):c.8575del (p.Gln2859fs) AND Hereditary cancer-predisposing syndrome

Germline classification:: Pathogenic (3 submissions)
Last evaluated:: Apr 26, 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:: RCV000130105.20

Allele description [Variation Report for NM_000059.4(BRCA2):c.8575del (p.Gln2859fs)]

NM_000059.4(BRCA2):c.8575del (p.Gln2859fs)

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.8575del (p.Gln2859fs)

HGVS:

NC_000013.11:g.32371043del
NG_012772.3:g.60564del
NM_000059.4:c.8575delMANE SELECT
NP_000050.3:p.Gln2859fs
LRG_293:g.60564del
NC_000013.10:g.32945180del
NC_000013.10:g.32945180delC
NC_000013.11:g.32371043delC
NM_000059.3:c.8575delC
NM_000059.4:c.8575del
NM_000059.4:c.8575delC
U43746.1:n.8803delC
p.Gln2859Lysfs*4
p.Q2859KFS*4

Nucleotide change:

8803delC

Links:

Breast Cancer Information Core (BIC) (BRCA2): 8803&base_change=del C; dbSNP: rs80359718

NCBI 1000 Genomes Browser:

rs80359718

Molecular consequence:

NM_000059.4:c.8575del - frameshift variant - [Sequence Ontology: SO:0001589]

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
SCV000184935	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Pathogenic (Sep 16, 2021)	germline	clinical testing	PubMed (12) [See all records that cite these PMIDs] 10359546, 16847550, 17148771, 21324516, 26360800, 27083775, 27433846, 29422015, 29446198, 31060593, 32570879, 33471991 Citation Link,
SCV000683986	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Apr 26, 2023)	germline	clinical testing	PubMed (11) [See all records that cite these PMIDs] 11304778, 16847550, 17148771, 18703817, 20104584, 21324516, 23704984, 25395318, 27083775, 27433846, 25741868
SCV002531961	Sema4, Sema4	criteria provided, single submitter (Sema4 Curation Guidelines)	Pathogenic (Aug 19, 2021)	germline	curation	PubMed (7) [See all records that cite these PMIDs] 16847550, 17148771, 20104584, 23704984, 29446198, 27433846, 26360800 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000184935

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Pathogenic
(Sep 16, 2021)

germline

clinical testing

PubMed (12)
[See all records that cite these PMIDs]

Citation Link,

SCV000683986

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Apr 26, 2023)

germline

clinical testing

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

SCV002531961

Sema4, Sema4

criteria provided, single submitter

(Sema4 Curation Guidelines)

Pathogenic
(Aug 19, 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

Prevalence of BRCA1 and BRCA2 gene mutations in patients with early-onset breast cancer.

Peto J, Collins N, Barfoot R, Seal S, Warren W, Rahman N, Easton DF, Evans C, Deacon J, Stratton MR.

J Natl Cancer Inst. 1999 Jun 2;91(11):943-9.

PubMed [citation]

PMID:: 10359546

Is RNASEL:p.Glu265* a modifier of early-onset breast cancer risk for carriers of high-risk mutations?

Nguyen-Dumont T, Teo ZL, Hammet F, Roberge A, Mahmoodi M, Tsimiklis H, Park DJ, Pope BJ, Lonie A, Kapuscinski MK, Mahmood K; ABCFR., Goldgar DE, Giles GG, Winship I, Hopper JL, Southey MC.

BMC Cancer. 2018 Feb 8;18(1):165. doi: 10.1186/s12885-018-4028-z.

PubMed [citation]

PMID:: 29422015
PMCID:: PMC5806316

See all PubMed Citations (18)

Details of each submission

From Ambry Genetics, SCV000184935.8

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (12)

Description

The c.8575delC pathogenic mutation, located in coding exon 19 of the BRCA2 gene, results from a deletion of one nucleotide at nucleotide position 8575, causing a translational frameshift with a predicted alternate stop codon (p.Q2859Kfs*4). This mutation has been reported in several individuals diagnosed with hereditary breast and ovarian cancer (HBOC) syndrome (Peto J et al. J. Natl. Cancer Inst. 1999 Jun;91:943-9; Risch HA et al. J Natl Cancer Inst, 2006 Dec;98:1694-706; Giannini G et al. Breast Cancer Res. Treat. 2006 Nov;100:83-91; Zhang S et al. Gynecol. Oncol. 2011 May;121:353-7; Seifert BA et al. Clin Cancer Res, 2016 Aug;22:4087-4094; Roed Nielsen H et al. Acta Oncol. 2016 Sep;55:38-44; Nguyen-Dumont T et al. BMC Cancer, 2018 02;18:165; Rebbeck TR et al. Hum Mutat, 2018 05;39:593-620; Petridis C et al. Breast Cancer Res, 2019 05;21:58; Dorling et al. N Engl J Med. 2021 02;384:428-439). This mutation has also been identified in 1/692 men with metastatic prostate cancer who were unselected for family history of cancer or age at diagnosis (Pritchard CC et al. N. Engl. J. Med. 2016 Aug;375:443-53), as well as an individual with lymphoma (Sprissler R et al. Cancers (Basel), 2020 Jun;12). Of note, this alteration is also designated as 8803delC in published literature. In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, 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, SCV000683986.4

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

Description

This variant deletes 1 nucleotide in exon 20 of the BRCA2 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in individuals affected with breast and/or ovarian cancer (PMID: 11304778, 16847550, 17148771, 18703817, 20104584, 21324516, 23704984, 25395318, 27083775), and prostate cancer (PMID: 27433846). This variant has been identified in 1/251220 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, SCV002531961.1

#	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: Oct 26, 2024

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