GeneBe

rs80359297

Variant names:

Variant summary

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

The NM_000059.4(BRCA2):​c.1654delT​(p.Ser552ProfsTer6) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,740 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

BRCA2
NM_000059.4 frameshift

Scores

Not classified

Clinical Significance

Pathogenic reviewed by expert panel P:13

Conservation

PhyloP100: 0.129
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]

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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 13-32333131-CT-C is Pathogenic according to our data. Variant chr13-32333131-CT-C is described in ClinVar as [Pathogenic]. Clinvar id is 51168.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr13-32333131-CT-C is described in Lovd as [Pathogenic]. Variant chr13-32333131-CT-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
BRCA2NM_000059.4 linkc.1654delT p.Ser552ProfsTer6 frameshift_variant Exon 10 of 27 ENST00000380152.8 NP_000050.3 P51587

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
BRCA2ENST00000380152.8 linkc.1654delT p.Ser552ProfsTer6 frameshift_variant Exon 10 of 27 5 NM_000059.4 ENSP00000369497.3 P51587
BRCA2ENST00000530893.7 linkc.1285delT p.Ser429ProfsTer6 frameshift_variant Exon 10 of 27 1 ENSP00000499438.2 A0A590UJI7
BRCA2ENST00000614259.2 linkn.1654delT non_coding_transcript_exon_variant Exon 9 of 26 2 ENSP00000506251.1 A0A7P0TAP7

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461740
Hom.:
0
Cov.:
35
AF XY:
0.00
AC XY:
0
AN XY:
727152
show subpopulations
Gnomad4 AFR exome
AF:
0.00
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:
8.99e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:13
Revision: reviewed by expert panel
LINK: link

Submissions by phenotype

Breast-ovarian cancer, familial, susceptibility to, 2 Pathogenic:4
Nov 27, 2012
Sharing Clinical Reports Project (SCRP)
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Jul 07, 2000
Breast Cancer Information Core (BIC) (BRCA2)
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

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 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. -

Hereditary breast ovarian cancer syndrome Pathogenic:3
Nov 19, 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.Ser552Profs*6) 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 not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with a personal and family history of breast cancer (PMID: 12942367). This variant is also known as 1882delT. ClinVar contains an entry for this variant (Variation ID: 51168). For these reasons, this variant has been classified as Pathogenic. -

Oct 22, 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.1654delT (p.Ser552ProfsX6) 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 251162 control chromosomes. c.1654delT has been reported in the literature in multiple individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (Kanaan_2003, Rebbeck_2018, Wu_2020). Five 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. -

Jan 31, 2014
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: research

- -

not provided Pathogenic:2
Nov 20, 2024
Quest Diagnostics Nichols Institute San Juan Capistrano
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The BRCA2 c.1654del (p.Ser552Profs*6) variant (also known as 1882delT) 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 (PMID: 12942367 (2003)), ovarian (PMID: 28888541 (2017)), and prostate cancer (PMID: 31948886 (2020)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Based on the available information, this variant is classified as pathogenic. -

Dec 13, 2019
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The BRCA2 c.1654delT; p.Ser552fs variant (rs80359297), also known as 1882delT, is reported in the literature in multiple individuals affected with breast and other cancers (Kanaan 2003, Olopade 2003). This variant is reported in ClinVar (Variation ID: 51168), and is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. This variant causes a frameshift by deleting a single nucleotide, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Additionally, several downstream truncating variants have been described in individuals with breast and/or ovarian cancer and are considered pathogenic (Kanaan 2003, Olopade 2003). Based on available information, this variant is considered to be pathogenic. References: Kanaan Y et al. Inherited BRCA2 mutations in African Americans with breast and/or ovarian cancer: a study of familial and early onset cases. Hum Genet. 2003 Oct;113(5):452-60. Olopade OI et al. Breast cancer genetics in African Americans. Cancer. 2003 Jan 1;97(1 Suppl):236-45. -

BRCA2-related cancer predisposition Pathogenic:1
Sep 16, 2024
All of Us Research Program, National Institutes of Health
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant deletes 1 nucleotide in exon 10 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 individuals affected with breast cancer (PMID: 12942367, 33471991; Leiden Open Variation Database DB-ID BRCA2_004255) and in four families among the CIMBA participants (PMID: 29446198, 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. -

BRCA2-related disorder Pathogenic:1
Mar 07, 2024
PreventionGenetics, part of Exact Sciences
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

The BRCA2 c.1654delT variant is predicted to result in a frameshift and premature protein termination (p.Ser552Profs*6). This variant has been reported in multiple individuals with breast and/or ovarian cancer (Table 2, Kanaan et al. 2003. PubMed ID: 12942367; Table S7, Lilyquist et al. 2017. PubMed ID: 28888541) and it has also been reported in an individual with prostate cancer (Table S7, Wu et al. 2020. PubMed ID: 31948886). This variant has not been reported in a large population database, indicating this variant is rare. This variant has been classified as pathogenic by an expert panel in the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/51168/). Frameshift variants in BRCA2 are expected to be pathogenic. This variant is interpreted as pathogenic. -

Familial cancer of breast Pathogenic:1
Jan 06, 2021
Baylor Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Pathogenic:1
Aug 02, 2022
Ambry Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.1654delT pathogenic mutation, located in coding exon 9 of the BRCA2 gene, results from a deletion of one nucleotide at nucleotide position 1654, causing a translational frameshift with a predicted alternate stop codon (p.S552Pfs*6). This mutation (designated as 1882delT) was reported in an African American woman diagnosed with breast cancer at age 43 (Kanaan Y et al. Hum. Genet. 2003 Oct;113:452-60). 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. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction

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

LitVar

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

Other links and lift over

dbSNP: rs80359297; hg19: chr13-32907268; API