NM_000059.4(BRCA2):c.8930del (p.Tyr2977fs) AND Hereditary breast ovarian cancer syndrome

Germline classification:: Pathogenic (3 submissions)
Last evaluated:: Dec 12, 2021
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:: RCV000496620.17

Allele description [Variation Report for NM_000059.4(BRCA2):c.8930del (p.Tyr2977fs)]

NM_000059.4(BRCA2):c.8930del (p.Tyr2977fs)

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.8930del (p.Tyr2977fs)

Other names:

9158delAStop2987

HGVS:

NC_000013.11:g.32379492del
NG_012772.3:g.69013del
NM_000059.4:c.8930delMANE SELECT
NP_000050.3:p.Tyr2977fs
LRG_293:g.69013del
NC_000013.10:g.32953629del
NC_000013.10:g.32953629delA
NM_000059.3:c.8930delA
p.Tyr2977Phefs*11
p.Tyr2977fs

Links:

dbSNP: rs869320799

NCBI 1000 Genomes Browser:

rs869320799

Molecular consequence:

NM_000059.4:c.8930del - 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
SCV000587977	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
SCV000635703	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Dec 12, 2021)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 24010542, 25395318, 20104584, 28492532
SCV000695193	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Jul 6, 2017)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 16912212, 24010542, 25395318 LabCorp Variant Classification Summary - May 2015.docx Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000587977

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

SCV000635703

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Dec 12, 2021)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

SCV000695193

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Pathogenic
(Jul 6, 2017)

germline

clinical testing

PubMed (3)
[See all records that cite these PMIDs]

LabCorp Variant Classification Summary - May 2015.docx

Citation Link

Help

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

Characterization of BRCA1 and BRCA2 deleterious mutations and variants of unknown clinical significance in unilateral and bilateral breast cancer: the WECARE study.

Borg A, Haile RW, Malone KE, Capanu M, Diep A, Törngren T, Teraoka S, Begg CB, Thomas DC, Concannon P, Mellemkjaer L, Bernstein L, Tellhed L, Xue S, Olson ER, Liang X, Dolle J, Børresen-Dale AL, Bernstein JL.

Hum Mutat. 2010 Mar;31(3):E1200-40. doi: 10.1002/humu.21202.

PubMed [citation]

PMID:: 20104584
PMCID:: PMC2928257

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. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

See all PubMed Citations (5)

Details of each submission

From Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto - The Canadian Open Genetics Repository (COGR), SCV000587977.1

#	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 Labcorp Genetics (formerly Invitae), Labcorp, SCV000635703.7

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

Description

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 225755). This variant is also known as 9158delA and c.8929_8929delA. This premature translational stop signal has been observed in individual(s) with breast and/or ovarian cancer (PMID: 24010542, 25395318). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Tyr2977Phefs*11) 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).

#	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 Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000695193.1

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

Description

Variant summary: The BRCA2 c.8930delA (p.Tyr2977Phefs) variant results in a premature termination codon, predicted to cause a truncated or absent BRCA2 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 (e.g. c.8961_8964delGAGT, c.8970G>A, and c.8978C>G). One in silico tool predicts a damaging outcome for this variant. This variant is absent in 121434 control chromosomes and has been reported in multiple affected individuals via publications. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified 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: Nov 3, 2024

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