chr13-32338758-CTGACA-C
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000059.4(BRCA2):c.4405_4409delGACAT(p.Asp1469LysfsTer11) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000275 in 1,455,516 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
Consequence
NM_000059.4 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| BRCA2 | ENST00000380152.8 | c.4405_4409delGACAT | p.Asp1469LysfsTer11 | frameshift_variant | Exon 11 of 27 | 5 | NM_000059.4 | ENSP00000369497.3 | ||
| BRCA2 | ENST00000530893.7 | c.4036_4040delGACAT | p.Asp1346LysfsTer11 | frameshift_variant | Exon 11 of 27 | 1 | ENSP00000499438.2 | |||
| BRCA2 | ENST00000614259.2 | n.4405_4409delGACAT | non_coding_transcript_exon_variant | Exon 10 of 26 | 2 | ENSP00000506251.1 |
Frequencies
GnomAD3 genomes
GnomAD4 exome AF: 0.00000275 AC: 4AN: 1455516Hom.: 0 AF XY: 0.00000138 AC XY: 1AN XY: 722822
GnomAD4 genome
ClinVar
Submissions by phenotype
Breast-ovarian cancer, familial, susceptibility to, 2 Pathogenic:5
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Variant allele predicted to encode a truncated non-functional protein. -
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The BRCA2 p.Asp1469LysfsX11 variant was not identified in the literature, nor was it identified in the NHLBI Exome Sequencing Project, Exome Aggregation Consortium (March 14, 2016), COSMIC, Clinvitae, BIC, BRCA Share UMD, ARUP Laboratories, LOVD Fanconi’s Anaemia and MutDB. The variant was identified DbSNP dbSNP (ID: rs397507331) as “With Pathogenic allele”. In the ClinVar database the variant was identified as pathogenic allele by the Sharing Clinical Reports Project, by GeneDx and Molecular Genetics Diagnostic Laboratory-Children Hospital of Eastern Ontario. The p.Asp1469LysfsX11deletion variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 1469 and leads to a premature stop codon 11 codons downstream. This alteration is then predicted to result in a truncated or absent protein and loss of function. Loss of function variants of the BRCA2 gene are an established mechanism of disease in hereditary breast and ovarian cancer and is the type of variant expected to cause the disorder. In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic. -
Hereditary breast ovarian cancer syndrome Pathogenic:3
Variant summary: BRCA2 c.4405_4409delGACAT (p.Asp1469LysfsX11) 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 247790 control chromosomes (gnomAD). c.4405_4409delGACAT has been reported in the literature in multiple individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (e.g. Wong-Brown_2015, Crawford_2017, Rebbeck_2018). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven other ClinVar submitters (including two expert panels; evaluation after 2014) cite the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
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This sequence change creates a premature translational stop signal (p.Asp1469Lysfs*11) 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 breast cancer (PMID: 25682074). ClinVar contains an entry for this variant (Variation ID: 37899). For these reasons, this variant has been classified as Pathogenic. -
not provided Pathogenic:2
This frameshift variant alters the translational reading frame of the BRCA2 mRNA and causes the premature termination of BRCA2 protein synthesis. This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In the published literature, the variant has been reported in individuals with breast cancer (PMIDs: 25682074 (2015), 28281021 (2017), 29446198 (2018), 34399810 (2021), and 33471991 (2021), see also LOVD (https://databases.lovd.nl/shared/variants/BRCA2)). Based on the available information, this variant is classified as pathogenic. -
Observed in individuals with a personal or family history consistent with pathogenic variants in this gene (Wong-Brown et al., 2015; Murali et al., 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; Not observed at significant frequency in large population cohorts (gnomAD); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Also known as 4633_4637del; This variant is associated with the following publications: (PMID: 34399810, 25682074, 28281021, 20104584, 32719484, 29446198) -
Hereditary cancer-predisposing syndrome Pathogenic:2
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. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in 3 individuals affected with breast cancer (PMID: 25682074, 33113089, 34399810), and has been identified in 6 families among the CIMBA participants (PMID: 29446198). In a large breast cancer case-control study conducted by the BRIDGES consortium, this variant was reported in 1/60466 cases and 1/53461 controls (OR=0.884, 95%CI: 0.055 to 14.136, p-value=1) (PMID: 33471991; Leiden Open Variation Database DB-ID BRCA2_004635). 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. -
The c.4405_4409delGACAT pathogenic mutation, located in coding exon 10 of the BRCA2 gene, results from a deletion of 5 nucleotides between positions 4405 and 4409, causing a translational frameshift with a predicted alternate stop codon (p.D1469Kfs*11). This alteration was reported in one individual from a cohort of 774 Australian and Polish women with triple negative breast cancer (Wong-Brown MW et al. Breast Cancer Res. Treat. 2015 Feb;150(1):71-80). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at