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

Germline classification:: Pathogenic (5 submissions)
Last evaluated:: Jan 24, 2024
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:: RCV000045564.26

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 breast ovarian cancer syndrome
Synonyms:: Hereditary breast and ovarian cancer syndrome; Hereditary breast and ovarian cancer; Hereditary breast and ovarian cancer syndrome (HBOC); See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0003582; MeSH: D061325; MedGen: C0677776; Orphanet: 145

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000073577	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 24, 2024)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 11304778, 20104584, 23704984, 26360800, 27083775, 27433846, 28492532
SCV000586983	Cancer Genetics and Genomics Laboratory, British Columbia Cancer Agency - The Canadian Open Genetics Repository (COGR)	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Apr 18, 2017)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000587961	Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto - The Canadian Open Genetics Repository (COGR)	no assertion criteria provided	Pathogenic (Jan 31, 2014)	germline	research
SCV001748680	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Jun 27, 2021)	germline	clinical testing	PubMed (8) [See all records that cite these PMIDs] 20104584, 18703817, 17148771, 23704984, 16847550, 11304778, 18779604, 29446198 Citation Link,
SCV004847921	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Oct 14, 2019)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 11304778, 27433846, 26360800, 25741868

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Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	research
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Germline Analysis from Tumor-Germline Sequencing Dyads to Identify Clinically Actionable Secondary Findings.

Seifert BA, O'Daniel JM, Amin K, Marchuk DS, Patel NM, Parker JS, Hoyle AP, Mose LE, Marron A, Hayward MC, Bizon C, Wilhelmsen KC, Evans JP, Earp HS 3rd, Sharpless NE, Hayes DN, Berg JS.

Clin Cancer Res. 2016 Aug 15;22(16):4087-4094. doi: 10.1158/1078-0432.CCR-16-0015. Epub 2016 Apr 15.

PubMed [citation]

PMID:: 27083775
PMCID:: PMC4987173

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240-242.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

See all PubMed Citations (13)

Details of each submission

From Invitae, SCV000073577.14

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

Description

This sequence change creates a premature translational stop signal (p.Gln2859Lysfs*4) in the BRCA2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in BRCA2 are known to be pathogenic (PMID: 20104584). This variant is present in population databases (rs80359718, gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with prostate cancer and breast cancer (PMID: 11304778, 20104584, 23704984, 26360800, 27083775, 27433846). This variant is also known as 8803delC. ClinVar contains an entry for this variant (Variation ID: 38169). For these reasons, this variant has been 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 Cancer Genetics and Genomics Laboratory, British Columbia Cancer Agency - The Canadian Open Genetics Repository (COGR), SCV000586983.1

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

#	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 Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto - The Canadian Open Genetics Repository (COGR), SCV000587961.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	research	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV001748680.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (8)

Description

Variant summary: BRCA2 c.8575delC (p.Gln2859LysfsX4) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 4e-06 in 251220 control chromosomes. c.8575delC has been reported in the literature in multiple individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (example, Rebbeck_2018). These data indicate that the variant is very likely to be associated with disease. Multiple clinical diagnostic laboratories, an expert panel (ENIGMA) and a consortium (CIMBA) have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was 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 Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV004847921.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

The p.Gln2859LysfsX4 variant in BRCA2 has been reported in >20 individuals with BRCA2-related cancers (Martin 2001, Pritchard 2016, Roed Nielsen 2016, BIC database). It was absent from large population databases. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 2859 and leads to a premature termination codon 4 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the BRCA2 gene is an established disease mechanism in autosomal dominant hereditary breast and ovarian cancer syndrome (HBOC). Additionally, this variant was classified as Pathogenic on Apr 22, 2016 by the ClinGen-approved ENIGMA expert panel (Variation ID: 38169). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant HBOC. ACMG/AMP Criteria applied: PVS1, PM2, PS4.

#	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: May 19, 2024

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