rs80359490

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_000059.4(BRCA2):c.5164_5165delAG(p.Ser1722TyrfsTer4) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000126 in 1,591,950 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★★). Synonymous variant affecting the same amino acid position (i.e. S1722S) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

BRCA2
NM_000059.4 frameshift

Scores

Not classified

Clinical Significance

Pathogenic reviewed by expert panel P:19

Conservation

PhyloP100: 0.604

Publications

32 publications found

Variant links:

Genes affected

BRCA2 (HGNC:1101): (BRCA2 DNA repair associated) Inherited mutations in BRCA1 and this gene, BRCA2, confer increased lifetime risk of developing breast or ovarian cancer. Both BRCA1 and BRCA2 are involved in maintenance of genome stability, specifically the homologous recombination pathway for double-strand DNA repair. The largest exon in both genes is exon 11, which harbors the most important and frequent mutations in breast cancer patients. The BRCA2 gene was found on chromosome 13q12.3 in human. The BRCA2 protein contains several copies of a 70 aa motif called the BRC motif, and these motifs mediate binding to the RAD51 recombinase which functions in DNA repair. BRCA2 is considered a tumor suppressor gene, as tumors with BRCA2 mutations generally exhibit loss of heterozygosity (LOH) of the wild-type allele. [provided by RefSeq, May 2020]

BRCA2 Gene-Disease associations (from GenCC):

breast-ovarian cancer, familial, susceptibility to, 2
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), ClinGen
Fanconi anemia complementation group D1
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, ClinGen, G2P
pancreatic cancer, susceptibility to, 2
Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
sarcoma
Inheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
hereditary breast ovarian cancer syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Fanconi anemia
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
medulloblastoma
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

BRCA2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 18 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 13-32339518-CAG-C is Pathogenic according to our data. Variant chr13-32339518-CAG-C is described in ClinVar as Pathogenic. ClinVar VariationId is 51791.Status of the report is reviewed_by_expert_panel, 3 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
BRCA2	NM_000059.4 link	c.5164_5165delAG	p.Ser1722TyrfsTer4	frameshift_variant	Exon 11 of 27	ENST00000380152.8	NP_000050.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
BRCA2	ENST00000380152.8 link	c.5164_5165delAG	p.Ser1722TyrfsTer4	frameshift_variant	Exon 11 of 27	5	NM_000059.4	ENSP00000369497.3
BRCA2	ENST00000530893.7 link	c.4795_4796delAG	p.Ser1599TyrfsTer4	frameshift_variant	Exon 11 of 27	1		ENSP00000499438.2
BRCA2	ENST00000614259.2 link	n.5164_5165delAG		non_coding_transcript_exon_variant	Exon 10 of 26	2		ENSP00000506251.1

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

152030

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

6.94e-7

AC:

AN:

1439920

Hom.:

AF XY:

0.00

AC XY:

AN XY:

715510

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32306

American (AMR)

AF:

0.00

AC:

AN:

40000

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25030

East Asian (EAS)

AF:

0.00

AC:

AN:

39510

South Asian (SAS)

AF:

0.00

AC:

AN:

81854

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52962

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5650

European-Non Finnish (NFE)

AF:

9.06e-7

AC:

AN:

1103210

Other (OTH)

AF:

0.00

AC:

AN:

59398

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00000658

AC:

AN:

152030

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74270

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41420

American (AMR)

AF:

0.00

AC:

AN:

15260

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3464

East Asian (EAS)

AF:

0.000193

AC:

AN:

5186

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10606

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67946

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:19

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 2

Pathogenic:9

Oct 02, 2015

Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 10, 2024

Department of Human Genetics, Hannover Medical School

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 13, 1997

Breast Cancer Information Core (BIC) (BRCA2)

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

May 27, 2024

Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PVS1; PM5_PTC_Strong -

Sep 08, 2016

Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)

Significance:Pathogenic

Review Status:reviewed by expert panel

Collection Method:curation

Variant allele predicted to encode a truncated non-functional protein. -

Sep 27, 2012

Sharing Clinical Reports Project (SCRP)

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jun 08, 2023

All of Us Research Program, National Institutes of Health

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant deletes 2 nucleotides in exon 11 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 is also known as 5392delAG in the literature. This variant has been reported in at least 10 individuals affected with breast and/or ovarian cancer (PMID: 9150154, 11391658, 19353265, 27907908, 29752822, 30972954, 32101877, 31957001, 33471991). This variant has been identified in 1/31360 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. -

Mar 02, 2020

BRCAlab, Lund University

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Dec 22, 2014

Counsyl

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

not provided

Pathogenic:3

Jan 20, 2023

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This frameshift variant alters the translational reading frame of the BRCA2 mRNA and causes the premature termination of BRCA2 protein synthesis. The frequency of this variant in the general population, 0.000032 (1/31360 chromosomes, http://gnomad.broadinstitute.org), is consistent with pathogenicity. In the published literature, the variant has been reported in individuals with breast and/or ovarian cancer (PMIDs: 32072338 (2020), 31957001 (2020), 30702160 (2019), 32101877 (2019), 30972954 (2019), 29752822 (2018), 19353265 (2009), 9150154 (1997)). Based on the available information, this variant is classified as pathogenic. -

Oct 23, 2020

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 30, 2024

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Not observed at significant frequency in large population cohorts (gnomAD); Also known as 5392_5393del; This variant is associated with the following publications: (PMID: 22160602, 27157322, 26848529, 28008555, 11391658, 36853301, 35864222, 35918668, 28324225, 27907908, 38167124, 28888541, 34697415, 9150154, 19353265, 24321281, 26757417, 26833046, 15744030, 26824983, 29566657, 28724667, 29752822, 29907814, 26295337, 30274973, 30078507, 30720243, 30702160, 30972954, 31957001, 32072338, 32467295, 31825140, 30787465, 32101877, 33461583) -

Familial cancer of breast

Pathogenic:3

Feb 11, 2024

Baylor Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Center for Precision Medicine, Meizhou People's Hospital

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Dec 21, 2021

MGZ Medical Genetics Center

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hereditary cancer-predisposing syndrome

Pathogenic:2

Feb 12, 2025

Ambry Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.5164_5165delAG pathogenic mutation, located in coding exon 10 of the BRCA2 gene, results from a deletion of two nucleotides at nucleotide positions 5164 to 5165, causing a translational frameshift with a predicted alternate stop codon (p.S1722Yfs*4). This mutation has been reported in multiple hereditary breast and ovarian cancer (HBOC) families, which include individuals with male breast cancer and pancreatic cancer (Håkansson S et al. Am. J. Hum. Genet. 1997 May;60:1068-78; Ganguly A et al. Am. J. Med. Genet. 2001 Jun;101:146-52; Kwong A et al. Breast Cancer Res. Treat. 2009 Oct;117:683-6; Schneegans SM et al. Fam. Cancer. 2012 Jun;11:181-8; Li D et al. J Exp Clin Cancer Res, 2013 Dec;32:102; Kim YC et al. Oncotarget 2016 Feb;7(8):9600-12; Ng PS et al. Clin. Genet. 2016 Oct:90:315-23; Chao A et al. Oncotarget 2016 Dec;7(51):85529-85541; Meisel C et al. Arch. Gynecol. Obstet. 2017 May;295(5):1227-1238; Sun J et al. Clin Cancer Res, 2017 Oct;23:6113-6119; Liang Y et al. Med Sci Monit, 2018 Apr;24:2465-2475;Bannon SA et al. Cancer Prev Res (Phila), 2018 11;11:679-686; Wang YA et al. BMC Cancer, 2018 03;18:315; Li A et al. Gynecol Oncol, 2018 10;151:145-152; Li JY et al. Int. J. Cancer. 2019 Jan;144(2):281-289; Wu H et al. Hum Hered, 2019 Feb;84:160-169; Deng H et al. Mol Genet Genomic Med, 2019 06;7:e672; Chen L et al. Breast Cancer Res Treat, 2020 Apr;180:759-766; Meng H et al. Int J Cancer, 2020 06;146:3044-3052; Dorling et al. N Engl J Med. 2021 02;384:428-439). 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. -

Apr 19, 2023

Color Diagnostics, LLC DBA Color Health

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Hereditary breast ovarian cancer syndrome

Pathogenic:2

Dec 29, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change creates a premature translational stop signal (p.Ser1722Tyrfs*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 (rs80359490, gnomAD 0.06%). This premature translational stop signal has been observed in individual(s) with breast and/or ovarian cancer (PMID: 9150154, 19353265, 22160602, 24321281, 26848529, 27157322). This variant is also known as 5392delAG and 5392-5393delAG. ClinVar contains an entry for this variant (Variation ID: 51791). For these reasons, this variant has been classified as Pathogenic. -

Jan 27, 2020

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

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: BRCA2 c.5164_5165delAG (p.Ser1722TyrfsX4) 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 was absent in 233676 control chromosomes. c.5164_5165delAG has been reported in the literature in multiple individuals affected with Hereditary Breast and Ovarian Cancer (eg. Bhaskaran_2019, Chao_2016, Hakansson_1997, Schneegans_2012). These data indicate that the variant is very likely to be associated with disease. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.60

Mutation Taster

=0/200

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over