NM_000059.4(BRCA2):c.9666del (p.Cys3222fs) AND not provided

Germline classification:: Pathogenic (3 submissions)
Last evaluated:: Mar 14, 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:: RCV001800351.15

Allele description [Variation Report for NM_000059.4(BRCA2):c.9666del (p.Cys3222fs)]

NM_000059.4(BRCA2):c.9666del (p.Cys3222fs)

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.9666del (p.Cys3222fs)

Other names:

9894delT

HGVS:

NC_000013.11:g.32398179del
NG_012772.3:g.87700del
NM_000059.4:c.9666delMANE SELECT
NM_000059.4:c.9666delT
NP_000050.3:p.Cys3222fs
LRG_293:g.87700del
NC_000013.10:g.32972316del
NC_000013.10:g.32972316delT
NM_000059.3:c.9666delT
NM_000059.4:c.9666del
U43746.1:n.9894delT
p.C3222WFS*27
p.Cys3222Trpfs*27

Links:

Breast Cancer Information Core (BIC) (BRCA2): 9894&base_change=del T; dbSNP: rs80359772

NCBI 1000 Genomes Browser:

rs80359772

Molecular consequence:

NM_000059.4:c.9666del - frameshift variant - [Sequence Ontology: SO:0001589]

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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phosphatidylcholine:ceramide cholinephosphotransferase 2 isoform X1 [Homo sapiens]
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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000296712	Quest Diagnostics Nichols Institute San Juan Capistrano	criteria provided, single submitter (Quest Diagnostics criteria)	Pathogenic (May 25, 2021)	unknown	clinical testing	PubMed (8) [See all records that cite these PMIDs] 11179017, 32885271, 29446198, 11897832, 29053726, 21913181, 26467025, 26295337
SCV001472863	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process)	Pathogenic (Aug 19, 2020)	germline	clinical testing	Citation Link,
SCV003915029	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Mar 14, 2023)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000296712

Quest Diagnostics Nichols Institute San Juan Capistrano

criteria provided, single submitter

(Quest Diagnostics criteria)

Pathogenic
(May 25, 2021)

unknown

clinical testing

PubMed (8)
[See all records that cite these PMIDs]

SCV001472863

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

criteria provided, single submitter

(ARUP Molecular Germline Variant Investigation Process)

Pathogenic
(Aug 19, 2020)

germline

clinical testing

Citation Link,

SCV003915029

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Pathogenic
(Mar 14, 2023)

germline

clinical testing

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	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Prevalence and penetrance of germline BRCA1 and BRCA2 mutations in a population series of 649 women with ovarian cancer.

Risch HA, McLaughlin JR, Cole DE, Rosen B, Bradley L, Kwan E, Jack E, Vesprini DJ, Kuperstein G, Abrahamson JL, Fan I, Wong B, Narod SA.

Am J Hum Genet. 2001 Mar;68(3):700-10. Epub 2001 Feb 15.

PubMed [citation]

PMID:: 11179017
PMCID:: PMC1274482

Multigene panel testing for hereditary breast and ovarian cancer in the province of Ontario.

Lerner-Ellis J, Mighton C, Lazaro C, Watkins N, Di Gioacchino V, Wong A, Chang MC, Charames GS.

J Cancer Res Clin Oncol. 2021 Mar;147(3):871-879. doi: 10.1007/s00432-020-03377-6. Epub 2020 Sep 3. Erratum in: J Cancer Res Clin Oncol. 2021 Aug;147(8):2487. doi: 10.1007/s00432-020-03399-0.

PubMed [citation]

PMID:: 32885271

See all PubMed Citations (8)

Details of each submission

From Quest Diagnostics Nichols Institute San Juan Capistrano, SCV000296712.2

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

Description

Although this frameshift variant occurs in the terminal exon of BRCA2 and is not expected to undergo nonsense-mediated decay, the variant removes the last 197 residues of the BRCA2 protein including a region functionally important for interaction with the RAD51 protein and is involved in recombination-mediated DNA repair (PMID: 17515903 (2007)). This variant has been reported in multiple individuals and families with breast/ovarian cancer (PMID: 32885271 (2021), 29053726 (2017), 21913181 (2012), 11897832 (2002), 11179017 (2001)). This variant has not been reported in large, multi-ethnic general populations. Based on the available information, this variant is classified as pathogenic.

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

From ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories, SCV001472863.1

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

Description

The BRCA2 c.9666delT; p.Cys3222fs variant (rs80359772) is reported in the literature in multiple individuals with a personal and/or family history of breast and/or ovarian cancer (Hamann 2002, Harter 2017, Risch 2001). This variant is found on a single chromosome in the Genome Aggregation Database (1/248958 alleles), indicating it is not a common polymorphism. This variant causes a frameshift by deleting a single nucleotide in the last exon of the BRCA2 gene. While this may not lead to nonsense-mediated decay, it is expected to create a truncated protein lacking the last 197 residues of the wildtype protein. Further, other truncating variants downstream of c.9666delT are reported in individuals with breast and/or ovarian cancer and are considered disease-causing (Dodova 2015, van der Hout 2006). Based on available information, the c.9666delT variant is considered to be pathogenic. References: Dodova RI et al. Spectrum and frequencies of BRCA1/2 mutations in Bulgarian high risk breast cancer patients. BMC Cancer. 2015;15:523. Hamann U et al. Contribution of BRCA2 germline mutations to hereditary breast/ovarian cancer in Germany. J Med Genet. 2002;39(3):E12. Harter P et al. Prevalence of deleterious germline variants in risk genes including BRCA1/2 in consecutive ovarian cancer patients (AGO-TR-1). PLoS One. 2017;12(10):e0186043. Risch HA et al. Prevalence and penetrance of germline BRCA1 and BRCA2 mutations in a population series of 649 women with ovarian cancer. Am J Hum Genet. 2001;68(3):700-710. van der Hout AH et al. A DGGE system for comprehensive mutation screening of BRCA1 and BRCA2: application in a Dutch cancer clinic setting. Hum Mutat. 2006;27(7):654-666.

#	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 GeneDx, SCV003915029.1

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

Description

Frameshift variant predicted to result in protein truncation in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Also known as 9894del; This variant is associated with the following publications: (PMID: 11179017, 29446198, 21913181, 11897832, 11802209, 17148771, 21324516, 32885271, 30720243, 28888541, 31567591, 29922827, 17026620, 18593900, 18607349, 26295337, 29053726, 22711857)

#	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

Last Updated: Oct 13, 2024

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