GeneBe

rs80359372

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.3167_3170delAAAA​(p.Gln1056ArgfsTer3) variant causes a frameshift change. The variant allele was found at a frequency of 0.000000687 in 1,455,482 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: 6.9e-7 ( 0 hom. )

Consequence

BRCA2
NM_000059.4 frameshift

Scores

Not classified

Clinical Significance

Pathogenic reviewed by expert panel P:13

Conservation

PhyloP100: 4.11
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]

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 13-32337521-CAAAA-C is Pathogenic according to our data. Variant chr13-32337521-CAAAA-C is described in ClinVar as [Pathogenic]. Clinvar id is 51413.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr13-32337521-CAAAA-C is described in Lovd as [Pathogenic]. Variant chr13-32337521-CAAAA-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
BRCA2NM_000059.4 linkc.3167_3170delAAAA p.Gln1056ArgfsTer3 frameshift_variant Exon 11 of 27 ENST00000380152.8 NP_000050.3 P51587

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
BRCA2ENST00000380152.8 linkc.3167_3170delAAAA p.Gln1056ArgfsTer3 frameshift_variant Exon 11 of 27 5 NM_000059.4 ENSP00000369497.3 P51587
BRCA2ENST00000530893.7 linkc.2798_2801delAAAA p.Gln933ArgfsTer3 frameshift_variant Exon 11 of 27 1 ENSP00000499438.2 A0A590UJI7
BRCA2ENST00000614259.2 linkn.3167_3170delAAAA non_coding_transcript_exon_variant Exon 10 of 26 2 ENSP00000506251.1 A0A7P0TAP7

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.00000405
AC:
1
AN:
246888
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
133440
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0000548
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:
6.87e-7
AC:
1
AN:
1455482
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
723456
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000253
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32
Bravo
AF:
0.00000378

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 29, 2001
Breast Cancer Information Core (BIC) (BRCA2)
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. -

Feb 09, 2016
Counsyl
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Hereditary breast ovarian cancer syndrome Pathogenic:4
Apr 01, 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.Gln1056Argfs*3) 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 (rs80359372, gnomAD 0.006%). This premature translational stop signal has been observed in individual(s) with undefined cancer and breast or ovarian cancer (PMID: 15131399, 18703817, 26187060, 26681312, 28724667). This variant is also known as 3395del4. ClinVar contains an entry for this variant (Variation ID: 51413). For these reasons, this variant has been classified as Pathogenic. -

Oct 15, 2018
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.3167_3170delAAAA (p.Gln1056ArgfsX3) 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. The variant allele was found at a frequency of 4.1e-06 in 241872 control chromosomes (gnomAD). c.3167_3170delAAAA has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer (Lubinski 2004, Palma 2008, Susswein 2015, Sun 2017). 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. Six 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 (5x) or likely pathogenic (1x). 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

- -

Jan 27, 2017
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The p.Gln1056fs variant in BRCA2 has been identified in at least 5 individuals w ith BRCA2-associated cancers (Lubinski 2004, Palma 2008, Susswein 2015, Breast C ancer Information Core (BIC)database). This variant has also been identified in 1/17212 East Asian chromosomes by the Genome Aggregation Database (gnomAD, http: //gnomad.broadinstitute.org/; dbSNP rs80359372). Please note that this frequency is low enough to be consistent with the frequency of hereditary breast and ovar ian cancer (HBOC) in the general population. This variant is predicted to cause a frameshift, which alters the protein?s amino acid sequence beginning at positi on 1056 and leads to a premature termination codon 3 amino acids downstream. Thi s alteration is then predicted to lead to a truncated or absent protein. Heteroz ygous loss of function of the BRCA2 gene is an established disease mechanism in individuals with HBOC. In addition, this variant was classified as Pathogenic on September 8, 2016 by the ClinGen-approved ENIGMA expert panel (ClinVar SCV00030 0592.2). In summary, this variant meets criteria to be classified as pathogenic for HBOC in an autosomal dominant manner based upon the predicted impact to the protein. -

not provided Pathogenic:2
Aug 30, 2023
Quest Diagnostics Nichols Institute San Juan Capistrano
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The BRCA2 c.3167_3170del (p.Gln1056Argfs*3) variant (also known as 3395del4) alters the translational reading frame of the BRCA2 mRNA and causes the premature termination of BRCA2 protein synthesis. In the published literature, this variant has been reported in multiple individuals with breast and/or ovarian cancer (PMIDs: 28724667 (2017), 26681312 (2015), 26187060 (2015), 18703817 (2008)). The frequency of this variant in the general population, 0.000055 (1/18258 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is consistent with pathogenicity. Based on the available information, this variant is classified as pathogenic. -

Jul 28, 2021
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; Not observed at 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; Observed in individuals with personal or family history of BRCA2-related cancers (Lubinski et al., 2004; Zhang et al., 2012; Sun et al., 2017); Also known as 3395_3398delAAAA or 3395del4; This variant is associated with the following publications: (PMID: 28724667, 30720243, 31825140, 30702160, 26187060, 21614564, 15131399) -

Hereditary cancer-predisposing syndrome Pathogenic:2
Oct 17, 2022
Color Diagnostics, LLC DBA Color Health
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant deletes 4 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 individuals with a personal or family history of breast, ovarian, or pancreatic cancer (PMID: 15131399, 21614564, 28724667, 29446198, 29785135, 35547873). This variant has been identified in 1/246888 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 14, 2023
Ambry Genetics
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.3167_3170delAAAA pathogenic mutation, located in coding exon 10 of the BRCA2 gene, results from a deletion of 4 nucleotides between nucleotide positions 3167 and 3170, causing a translational frameshift with a predicted alternate stop codon ( p.Q1056Rfs*3). This mutation, designated as 3395del4, was identified in a series of suspected HBOC families (Lubinski J et al, Fam. Cancer 2004;3(1):1-10). 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
Oct 20, 2021
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: rs80359372; hg19: chr13-32911658; API