NM_000059.4(BRCA2):c.8924del (p.Val2975fs) AND Hereditary cancer-predisposing syndrome

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: May 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:: RCV001525346.12

Allele description [Variation Report for NM_000059.4(BRCA2):c.8924del (p.Val2975fs)]

NM_000059.4(BRCA2):c.8924del (p.Val2975fs)

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.8924del (p.Val2975fs)

Other names:

9152delT

HGVS:

NC_000013.11:g.32379486del
NG_012772.3:g.69007del
NM_000059.4:c.8924delMANE SELECT
NP_000050.3:p.Val2975fs
LRG_293:g.69007del
NC_000013.10:g.32953623del
NC_000013.10:g.32953623delT
NM_000059.3:c.8924delT
p.Val2975Glufs*13
p.Val2975fs

Links:

dbSNP: rs397508020

NCBI 1000 Genomes Browser:

rs397508020

Molecular consequence:

NM_000059.4:c.8924del - 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

Recent activity

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green fluorescent GFP-like protein [Oxypora echinata]
green fluorescent GFP-like protein [Oxypora echinata]
gi|78059158|gb|ABB17956.1|

Protein
JGI_XZG27632.rev NIH_XGC_tropGas7 Xenopus tropicalis cDNA clone IMAGE:7543174 3'...
JGI_XZG27632.rev NIH_XGC_tropGas7 Xenopus tropicalis cDNA clone IMAGE:7543174 3', mRNA sequence
gi|57274378|gnl|dbEST|27080409|gb|C 47.1|

Nucleotide
DC043068 Osada Taira anterior endomesoderm (AEM) pCS105 cDNA library Xenopus lae...
DC043068 Osada Taira anterior endomesoderm (AEM) pCS105 cDNA library Xenopus laevis cDNA clone xlk123e13ex 5', mRNA sequence
gi|118985181|gnl|dbEST|43285704|dbj 3068.1|

Nucleotide

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001735415	Color Diagnostics, LLC DBA Color Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Oct 5, 2020)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002687358	Ambry Genetics	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Pathogenic (May 12, 2021)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 20383589, 25948282, 29446198 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001735415

Color Diagnostics, LLC DBA Color Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Oct 5, 2020)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

SCV002687358

Ambry Genetics

criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)

Pathogenic
(May 12, 2021)

germline

clinical testing

PubMed (3)
[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

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Novel germline mutations in BRCA2 gene among breast and breast-ovarian cancer families from Poland.

Balabas A, Skasko E, Nowakowska D, Niwinska A, Blecharz P.

Fam Cancer. 2010 Sep;9(3):267-74. doi: 10.1007/s10689-010-9338-5.

PubMed [citation]

PMID:: 20383589

See all PubMed Citations (4)

Details of each submission

From Color Diagnostics, LLC DBA Color Health, SCV001735415.1

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

Description

This variant deletes 1 nucleotide in exon 22 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. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with breast cancer (PMID: 20383589, 22864640, 32614418). 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, SCV002687358.2

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

Description

The c.8924delT pathogenic mutation, located in coding exon 21 of the BRCA2 gene, results from a deletion of one nucleotide at nucleotide position 8924, causing a translational frameshift with a predicted alternate stop codon (p.V2975Efs*13). This alteration has been identified in multiple hereditary breast/ovarian cancer cohorts, including in an individual with male breast cancer and a family history of ovarian and esophageal cancer (Balabas A et al. Fam Cancer, 2010 Sep;9:267-74; Kluska A et al. BMC Med Genomics, 2015 May;8:19; Rebbeck TR et al. Hum Mutat, 2018 05;39:593-620). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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

Last Updated: Nov 3, 2024

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