GeneBe

rs397507265

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.1205delG​(p.Gly402ValfsTer2) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,230 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: 𝑓 0.0000066 ( 0 hom., cov: 32)

Consequence

BRCA2
NM_000059.4 frameshift

Scores

Not classified

Clinical Significance

Pathogenic reviewed by expert panel P:13

Conservation

PhyloP100: 0.594
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 13-32332681-AG-A is Pathogenic according to our data. Variant chr13-32332681-AG-A is described in ClinVar as [Pathogenic]. Clinvar id is 37730.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr13-32332681-AG-A is described in Lovd as [Pathogenic]. Variant chr13-32332681-AG-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
BRCA2NM_000059.4 linkc.1205delG p.Gly402ValfsTer2 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.1205delG p.Gly402ValfsTer2 frameshift_variant Exon 10 of 27 5 NM_000059.4 ENSP00000369497.3 P51587
BRCA2ENST00000530893.7 linkc.836delG p.Gly279ValfsTer2 frameshift_variant Exon 10 of 27 1 ENSP00000499438.2 A0A590UJI7
BRCA2ENST00000614259.2 linkn.1205delG non_coding_transcript_exon_variant Exon 9 of 26 2 ENSP00000506251.1 A0A7P0TAP7

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152230
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000241
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
GnomAD4 exome
Cov.:
35
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152230
Hom.:
0
Cov.:
32
AF XY:
0.0000134
AC XY:
1
AN XY:
74372
show subpopulations
Gnomad4 AFR
AF:
0.0000241
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

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
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

- -

Oct 08, 2018
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.1205delG (p.Gly402Valfs*2) variant in the BRCA2 gene is predicted to introduce a premature translation termination codon. This variant has been reported in one patient with triple-negative breast cancer (PMID 25428789), one patient with high likelihood of being a mutation carrier predicted by BRCAPRO statistical modeling (PMID 16234499), and multiple individuals who were referred for clinical testing in other clinical labs. This variant is not observed in gnomAD. Therefore, the c.1205delG (p.Gly402Valfs*2) variant in the BRCA2 gene is classified as pathogenic. -

Mar 11, 2008
Sharing Clinical Reports Project (SCRP)
Significance: Pathogenic
Review Status: no assertion criteria provided
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:4
Jul 13, 2018
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The p.Gly402ValfsX2 variant in BRCA2 has been reported in at least 3 African Ame rican individuals with a personal or family history of breast and/or ovarian can cer (Nanda 2005, Lynce 2015, Churpek 2015). This variant has been identified in 1/8734 African chromosomes by the Genome Aggregation Database (gnomAD, http://gn omad.broadinstitute.org). This variant is predicted to cause a frameshift, which alters the protein?s amino acid sequence beginning at position 402 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 functi on of the BRCA2 gene is an established disease mechanism in hereditary breast an d ovarian cancer (HBOC). In addition, this variant was classified as Pathogenic on Sept 8, 2016 by the ClinGen-approved ENIGMA expert panel (ClinVar SCV00030040 6.2). In summary, this variant meets criteria to be classified as pathogenic for HBOC in an autosomal dominant manner based upon the presence in probands and th e predicted impact on the protein. ACMG/AMP Criteria applied: PVS1, PM2, PS4_Sup porting. -

Jan 19, 2017
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Variant summary: The BRCA2 c.1205delG (p.Gly402Valfs) variant results in a premature termination codon, predicted to cause a truncated or absent BRCA2 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 (e.g c.1257delT, p.Cys419fs). One in silico tool predicts a damaging outcome for this variant. This variant is absent in 120776 control chromosomes. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is 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

- -

Nov 15, 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.Gly402Valfs*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 (rs397507265, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with breast and/or ovarian cancer (PMID: 16234499, 25428789, 26250392). This variant is also known as 1433delG. ClinVar contains an entry for this variant (Variation ID: 37730). For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:2
Dec 31, 2019
Quest Diagnostics Nichols Institute San Juan Capistrano
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The variant results in a shift of the reading frame, and is therefore predicted to result in the loss of a functional protein. Found in at least one patient with expected phenotype for this gene, and found in general population data at a frequency that is consistent with pathogenicity. -

Mar 28, 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; Observed in individuals with personal and/or family history consistent with pathogenic variants in this gene (PMID: 16234499, 25428789, 26250392, 32832836); Not observed at significant frequency in large population cohorts (gnomAD); Also known as 1433delG; This variant is associated with the following publications: (PMID: 25428789, 26250392, 16234499, 26295337, 26681312, 30720243, 31447099, 32832836) -

BRCA2-related disorder Pathogenic:1
May 23, 2024
PreventionGenetics, part of Exact Sciences
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: clinical testing

The BRCA2 c.1205delG variant is predicted to result in a frameshift and premature protein termination (p.Gly402Valfs*2). This variant (also known as c.1433delG) has been reported in individuals with a personal or family history of breast and/or ovarian cancer (see for example, Nanda et al. 2005. PubMed ID: 16234499; Lynce et al. 2015. PubMed ID: 26250392; Churpek et al. 2015. PubMed ID: 25428789; eMERGE Consortium. 2019. PubMed ID: 31447099. Table S10). This variant was also identified in 1/10030 patients referred for cancer panel testing (Susswein et al. PubMed ID: 26681312. Table S1). This variant is reported in 0.011% of alleles in individuals of African descent in gnomAD and is interpreted as pathogenic by the vast majority of submitters in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/37730/). Frameshift variants in BRCA2 are expected to be pathogenic. This variant is interpreted as pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:1
Dec 23, 2022
Ambry Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.1205delG pathogenic mutation, located in coding exon 9 of the BRCA2 gene, results from a deletion of one nucleotide at nucleotide position 1205, causing a translational frameshift with a predicted alternate stop codon (p.G402Vfs*2). This mutation has been reported in high-risk African-American breast cancer patients (Nanda R et al. JAMA. 2005; 294:1925-33; Churpek JE et al. Breast Cancer Res Treat. 2015 Jan;149(1):31-9). This alteration was identified in 1/10030 consecutive patients referred for evaluation by an NGS hereditary cancer panel (Susswein LR et al. Genet. Med., 2016 08;18:823-32). Of note, this mutation is also designated as 1433delG 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. -

Familial cancer of breast Pathogenic:1
Mar 15, 2022
Baylor Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

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: rs397507265; hg19: chr13-32906818; API