rs80359525

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_000059.4(BRCA2):c.5616_5620del(p.Lys1872AsnfsTer2) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000248 in 1,610,278 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. S1871S) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

BRCA2
NM_000059.4 frameshift

Scores

Not classified

Clinical Significance

Pathogenic reviewed by expert panel P:23U:1

Conservation

PhyloP100: 1.50

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 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 13-32339965-CAGTAA-C is Pathogenic according to our data. Variant chr13-32339965-CAGTAA-C is described in ClinVar as [Pathogenic]. Clinvar id is 51892.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr13-32339965-CAGTAA-C is described in Lovd as [Pathogenic]. Variant chr13-32339965-CAGTAA-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
BRCA2	NM_000059.4 linkuse as main transcript	c.5616_5620del	p.Lys1872AsnfsTer2	frameshift_variant	11/27	ENST00000380152.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
BRCA2	ENST00000380152.8 linkuse as main transcript	c.5616_5620del	p.Lys1872AsnfsTer2	frameshift_variant	11/27	5	NM_000059.4	A2

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152108

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

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

GnomAD3 exomes

AF:

0.00000404

AC:

AN:

247384

Hom.:

AF XY:

0.00000748

AC XY:

AN XY:

133726

show subpopulations

Gnomad AFR exome

AF:

0.0000622

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1458170

Hom.:

AF XY:

0.00000138

AC XY:

AN XY:

725160

show subpopulations

Gnomad4 AFR exome

AF:

0.0000301

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.00e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152108

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74282

show subpopulations

Gnomad4 AFR

AF:

0.0000483

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000491

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:23Uncertain:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 2

Pathogenic:7

Likely pathogenic, criteria provided, single submitter	clinical testing	Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	Nov 21, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	Oct 02, 2015	- -
Pathogenic, no assertion criteria provided	clinical testing	Breast Cancer Information Core (BIC) (BRCA2)	May 29, 2002	- -
Pathogenic, reviewed by expert panel	curation	Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	Sep 08, 2016	Variant allele predicted to encode a truncated non-functional protein. -
Pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Feb 08, 2017	- -
Pathogenic, no assertion criteria provided	clinical testing	Sharing Clinical Reports Project (SCRP)	May 01, 2012	- -
Pathogenic, criteria provided, single submitter	research	HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	Sep 11, 2018	- -

Hereditary breast ovarian cancer syndrome

Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 26, 2024	This sequence change creates a premature translational stop signal (p.Lys1872Asnfs*2) 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 (rs763069721, gnomAD 0.007%). This premature translational stop signal has been observed in individual(s) with breast cancer (PMID: 15533909, 20104584, 24742220, 25428789, 26681312, 28008555). This variant is also known as 5844del5. ClinVar contains an entry for this variant (Variation ID: 51892). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 17, 2021	Variant summary: BRCA2 c.5616_5620delAGTAA (p.Lys1872AsnfsX2) 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 247384 control chromosomes. c.5616_5620delAGTAA has been reported in the literature in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (Borg_2010, Caux-Moncoutier_2011, Hernandez_2014, Pal_2004, Pal_2016, etc.). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. 13 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/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	research	Genetics Program, Instituto Nacional de Cancer	Nov 01, 2021	- -
Pathogenic, no assertion criteria provided	research	Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	Jan 31, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	Jul 02, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jun 07, 2023	The p.Lys1872AsnfsX2 variant in BRCA2 has been reported in >10 individuals with BRCA2 associated cancers (Pal 2004 PMID:15533909, Borg 2010 PMID:20104584, Hernandez 2014 PMID:24742220, Churpek 2015 PMID:25428789, Susswein 2015 PMID:26681312, Sun 2017 PMID:28724667, Cock-Rada 2018 PMID:28528518, Breast Cancer Information Core (BIC) database: https://research.nhgri.nih.gov/bic/). This variant has also been identified in 0.005% (2/41432) of African/African American chromosomes by gnomAD (http://gnomad.broadinstitute.org, v3.1.2). This frequency is low enough to be consistent with the frequency of hereditary breast and ovarian cancer (HBOC) in the general population. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 1872 and leads to a premature termination codon 2 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Heterozygous loss of function of the BRCA2 gene is an established disease mechanism for HBOC. Additionally, this variant was classified as pathogenic on Sep 08, 2016 by the ClinGen-approved ENIGMA expert panel (Variation ID 51892). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant. ACMG/AMP criteria applied: PS4_Moderate, PM2_Supporting, PVS1. -

not provided

Pathogenic:4Uncertain:1

Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, FAU Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg	Nov 22, 2023	This variant has been identified by standard clinical testing. female patient with breast cancer Selected ACMG criteria: Pathogenic (I):PP5;PM2;PVS1 -
Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jul 12, 2023	The BRCA2 c.5616_5620del (p.Lys1872Asnfs*2) variant alters the translational reading frame of the BRCA2 mRNA and causes the premature termination of BRCA2 protein synthesis. This variant has been reported in the published literature in individuals with breast cancer (PMID: 36329109 (2022), 32318955 (2020), 32866190 (2020), 30128899 (2018), 28528518 (2017), 28724667 (2017), 26681312 (2015), 25428789 (2015), 24742220 (2014), 20104584 (2010), 15533909 (2004)) and male breast cancer (PMID: 28008555 (2017)). The frequency of this variant in the general population, 0.000004 (1/247384 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is consistent with pathogenicity. Based on the available information, this variant is classified as pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Mar 09, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Feb 24, 2021	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; Observed in individuals with BRCA2-related cancers (Pal 2004, Borg 2010, Wang 2012, Hernandez 2014, McFarland 2015, Natarajan 2016, Cock-Rada 2017, Pritzlaff 2017, Ademuyiwa 2019); Not observed at a significant frequency in large population cohorts (Lek 2016); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; This variant is associated with the following publications: (PMID: 26681312, 15533909, 24742220, 20104584, 21643751, 25726062, 28008555, 27831900, 25428789, 28528518, 28724667, 26295337, 26287763, 30128899, 29907814, 30720243, 31325073, 31415627, 31019283, 32318955, 31825140) -

Hereditary cancer-predisposing syndrome

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jan 31, 2022	This variant deletes 5 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 has been reported in more than 10 individuals affected with breast cancer and 1 individual affected with prostate cancer (PMID: 15533909, 20104584, 24742220, 25428789, 26681312, 27831900, 28008555, 28528518, 30257646, Color internal data). This variant has been identified in 1/247384 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Dec 20, 2021	The c.5616_5620delAGTAA pathogenic mutation, located in coding exon 10 of the BRCA2 gene, results from a deletion of 5 nucleotides at nucleotide positions 5616 to 5620, causing a translational frameshift with a predicted alternate stop codon (p.K1872Nfs*2). This pathogenic mutation has been reported in multiple individuals with hereditary breast and/or ovarian cancer, including male breast cancer (Pal T et al. Cancer Epidemiol. Biomarkers Prev. 2004 Nov;13:1794-9; Hernández JE et al. Hered. Cancer Clin. Pract. 2014 Apr;12(1):11; Churpek JE et al. Breast Cancer Res Treat, 2015 Jan;149:31-9; Susswein LR et al. Genet. Med. 2016 Aug;18:823-32; Pritzlaff M et al. Breast Cancer Res. Treat. 2017 Feb;161:575-586; Sun J et al. Clin. Cancer Res. 2017 Oct;23(20):6113-6119; Choi MC et al. Int J Gynecol Cancer, 2018 02;28:308-315; Marchetti C et al. Ann Surg Oncol, 2018 Nov;25:3701-3708; Hoyer J et al. BMC Cancer, 2018 Sep;18:926; Ademuyiwa FO et al. Breast Cancer Res Treat, 2019 Nov;178:151-159; Vargas E et al. Oncologist, 2019 07;24:e475-e479; Zeng C et al. Breast Cancer Res Treat, 2020 Jun;181:465-473; Bishop MR et al. PLoS One, 2020 Aug;15:e0238295). Of note, this alteration is also designated as 5844del5 and c.5611_5615del in published literature. 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. -
Pathogenic, criteria provided, single submitter	curation	Sema4, Sema4	Dec 22, 2021	- -

Medulloblastoma;C0346153:Familial cancer of breast;C0376358:Malignant tumor of prostate;C1838457:Fanconi anemia complementation group D1;C2675520:Breast-ovarian cancer, familial, susceptibility to, 2;C2751641:Glioma susceptibility 3;C3150546:Pancreatic cancer, susceptibility to, 2;CN033288:Wilms tumor 1

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Mar 10, 2022

- -

BRCA2-Related Disorders

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

DASA

Mar 05, 2022

The c.5616_5620del ;p.(Lys1872Asnfs*2) is a null frameshift variant (NMD) in the BRCA2 gene and predicts alteration of the nonsense-mediate decay - NMD is present in a relevant exon to the transcript - PVS1. This sequence change has been observed in affected individual(s) and ClinVar contains an entry for this variant (Clinvar ID: 51892; PMID: 28008555; PMID: 26287763; PMID: 26681312; PMID: 27831900; PMID: 20104584)PS4. The variant is present at low allele frequencies population databases (rs80359525 – gnomAD 0.0001315%; ABraOM no frequency - http://abraom.ib.usp.br.) - PM2_supporting. In summary, the currently available evidence indicates that the variant is pathogenic. -

Familial cancer of breast

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Feb 23, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over