rs80359436
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Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000059.4(BRCA2):c.4258delG(p.Asp1420fs) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000138 in 1,444,516 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: 33)
Exomes 𝑓: 0.0000014 ( 0 hom. )
Consequence
BRCA2
NM_000059.4 frameshift
NM_000059.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 0.305
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 13-32338612-AG-A is Pathogenic according to our data. Variant chr13-32338612-AG-A is described in ClinVar as [Pathogenic]. Clinvar id is 51617.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr13-32338612-AG-A is described in Lovd as [Pathogenic]. Variant chr13-32338612-AG-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
BRCA2 | NM_000059.4 | c.4258delG | p.Asp1420fs | frameshift_variant | 11/27 | ENST00000380152.8 | NP_000050.3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
BRCA2 | ENST00000380152.8 | c.4258delG | p.Asp1420fs | frameshift_variant | 11/27 | 5 | NM_000059.4 | ENSP00000369497.3 | ||
BRCA2 | ENST00000530893.7 | c.3889delG | p.Asp1297fs | frameshift_variant | 11/27 | 1 | ENSP00000499438.2 | |||
BRCA2 | ENST00000614259.2 | n.4258delG | non_coding_transcript_exon_variant | 10/26 | 2 | ENSP00000506251.1 |
Frequencies
GnomAD3 genomes Cov.: 33
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GnomAD3 exomes AF: 0.00000819 AC: 2AN: 244196Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 132480
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GnomAD4 exome AF: 0.00000138 AC: 2AN: 1444516Hom.: 0 Cov.: 35 AF XY: 0.00 AC XY: 0AN XY: 715414
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GnomAD4 genome Cov.: 33
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:15
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
Breast-ovarian cancer, familial, susceptibility to, 2 Pathogenic:7
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 | BRCAlab, Lund University | Aug 26, 2022 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Department of Medical Genetics, Oslo University Hospital | Jul 01, 2015 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Sharing Clinical Reports Project (SCRP) | Apr 17, 2012 | - - |
Likely pathogenic, criteria provided, single submitter | literature only | Counsyl | Oct 20, 2014 | - - |
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, no assertion criteria provided | clinical testing | Breast Cancer Information Core (BIC) (BRCA2) | May 29, 2002 | - - |
not provided Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jul 05, 2017 | This deletion of one nucleotide in BRCA2 is denoted c.4258delG at the cDNA level and p.Asp1420IlefsX28 (D1420IfsX28) at the protein level. The normal sequence, with the base that is deleted in brackets, is TAAAA[delG]ATTT. The deletion causes a frameshift which changes an Aspartic Acid to an Isoleucine at codon 1420, and creates a premature stop codon at position 28 of the new reading frame. This variant is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. BRCA2 c.4258delG has been observed in association with breast cancer and is known to be a pathogenic founder variant in the Swedish population (Hakansson 1997, Haraldsson 1998, Loman 2001, Janavicius 2010). We consider this variant to be pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Clinical Genetics Laboratory, Skane University Hospital Lund | Sep 18, 2023 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Aug 15, 2023 | - - |
Hereditary cancer-predisposing syndrome Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 13, 2023 | The c.4258delG pathogenic mutation is located in coding exon 10 of the BRCA2 gene. This results from a deletion of one nucleotide at nucleotide position 4258, causing a translational frameshift with a predicted alternate stop codon (p.D1420Ifs*28). This mutation has been reported in two unrelated Scandinavian families with histories of breast, cervical, and pancreatic cancers, as well as in tumor tissue from three unrelated males diagnosed with breast cancer (Håkansson S et al. Am J Hum Genet. 1997 May;60(5):1068-78). The c.4258delG pathogenic mutation is commonly found in the Swedish population and has been reported as a Swedish founder mutation (Janaviius R. EPMA J. 2010 Sep;1(3):397-412). Of note, this mutation is also designated as 4486delG. 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 | clinical testing | Color Diagnostics, LLC DBA Color Health | Mar 09, 2022 | This variant deletes 1 nucleotide 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 a known Swedish founder mutation and has been reported in 5 individuals affected with breast cancer, including 3 male individuals, and has also been observed in unaffected individuals (PMID: 10615237, 11504767, 33471991). This variant has been identified in 19 families among the CIMBA participants (PMID: 29446198). This variant has been identified in 2/244196 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. - |
Hereditary breast ovarian cancer syndrome Pathogenic:2
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 | Labcorp Genetics (formerly Invitae), Labcorp | Jun 26, 2022 | For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 51617). This variant is also known as c.4486delG. This premature translational stop signal has been observed in individual(s) with breast cancer (PMID: 9150154). This variant is present in population databases (rs80359436, gnomAD 0.002%). This sequence change creates a premature translational stop signal (p.Asp1420Ilefs*28) 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). - |
not specified Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Aug 06, 2018 | The BRCA2 c.4258delG; p.Asp1420fs variant (rs80359436), also known as 4486delG, is reported in the literature in families with breast cancer (Hakansson 1997, Winter 2016), and is commonly found in the Swedish population (Janavicius 2010). This variant is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 51617), and is observed in the general population with a low overall allele frequency of 0.0008% (2/240284 alleles) in the Genome Aggregation Database. This variant deletes a single nucleotide causing a frameshift, and is predicted to result in a truncated protein or absent transcript. Based on the above information, this variant is considered pathogenic. REFERENCES Hakansson S et al. Moderate frequency of BRCA1 and BRCA2 germ-line mutations in Scandinavian familial breast cancer. Am J Hum Genet. 1997 May;60(5):1068-78. Janavicius R. Founder BRCA1/2 mutations in the Europe: implications for hereditary breast-ovarian cancer prevention and control. EPMA J. 2010 Sep;1(3):397-412. Winter C et al. Targeted sequencing of BRCA1 and BRCA2 across a large unselected breast cancer cohort suggests that one-third of mutations are somatic. Ann Oncol. 2016 Aug;27(8):1532-8. - |
Computational scores
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Details are displayed if max score is > 0.2
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