rs397507402
Variant summary
Our verdict is Pathogenic. Variant got 22 ACMG points: 22P and 0B. PVS1PS1PM2PP5_Very_Strong
The NM_000059.4(BRCA2):c.8414_8416delTATinsC(p.Leu2805SerfsTer6) variant causes a frameshift, missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Pathogenic in Lovd. Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_000059.4 frameshift, missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 22 ACMG points.
Transcripts
RefSeq
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| BRCA2 | ENST00000380152.8 | c.8414_8416delTATinsC | p.Leu2805SerfsTer6 | frameshift_variant, missense_variant | Exon 19 of 27 | 5 | NM_000059.4 | ENSP00000369497.3 | ||
| BRCA2 | ENST00000530893.7 | c.8045_8047delTATinsC | p.Leu2682SerfsTer6 | frameshift_variant, missense_variant | Exon 19 of 27 | 1 | ENSP00000499438.2 | |||
| BRCA2 | ENST00000614259.2 | n.*472_*474delTATinsC | non_coding_transcript_exon_variant | Exon 18 of 26 | 2 | ENSP00000506251.1 | ||||
| BRCA2 | ENST00000614259 | n.*472_*474delTATinsC | 3_prime_UTR_variant | Exon 18 of 25 | 2 | ENSP00000506251.1 |
Frequencies
GnomAD3 genomes
GnomAD4 genome
ClinVar
Submissions by phenotype
Breast-ovarian cancer, familial, susceptibility to, 2 Pathogenic:3
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Variant allele predicted to encode a truncated non-functional protein. -
not provided Pathogenic:2
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; Observed in individuals with BRCA2-related cancers (PMID: 26150619, 36315513); Also known as 8642del3insC; This variant is associated with the following publications: (PMID: 26150619, 12942367, 29446198, 30787465, 36315513) -
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 symptomatic patient, and not found in general population data. -
Hereditary cancer-predisposing syndrome Pathogenic:2
This variant deletes 3 nucleotides and inserts 1 nucleotide in exon 19 of the BRCA2 gene, creating a frameshift and a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. To our knowledge, functional assays have not been performed for this variant. This variant has been reported in an individual affected with breast cancer, prostate cancer, and gastrointestinal stromal tumor and with a family history of male and female breast cancer (PMID: 26150619). 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. Based on available evidence, this variant is classified as Pathogenic. -
The c.8414_8416delTATinsC pathogenic mutation, located in coding exon 18 of the BRCA2 gene, results from the deletion of 3 nucleotides and insertion of one nucleotide causing a translational frameshift with a predicted alternate stop codon (p.L2805Sfs*6). This pathogenic mutation, referred to as 8642del3insC, was detected in a male patient who had a personal history of prostate cancer, breast cancer, and GIST (Waisbren J et al. BMJ Case Rep. 2015 Jul;2015). This alteration was identified in a large, worldwide study of BRCA1/2 mutation positive families (Rebbeck TR et al. Hum Mutat, 2018 05;39:593-620). 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. -
Hereditary breast ovarian cancer syndrome Pathogenic:2
This sequence change deletes 3 nucleotides and inserts 1 nucleotide in exon 19 of the BRCA2 mRNA (c.8414_8416delinsC), causing a frameshift at codon 2805. This creates a premature translational stop signal (p.Leu2805Serfs*6) and is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). A set of variants that result in a similar protein effect have been reported in the literature in an individual affected with early-onset breast cancer. In this individual, two variants were described - a frameshift, c.8415_8416delAT (called 8643delAT), and a missense, c.8416T>C (called T8642C). If these two variants are in cis, they would result in the same variant observed here (c.8414_8416delinsC). However, the phase of these variants was not determined in the reported individual (PMID: 12942367). ClinVar contains an entry for this variant (Variation ID: 38159). Loss-of-function variants in BRCA2 are known to be pathogenic (PMID: 20104584). For these reasons, this variant has been classified as Pathogenic. -
Variant summary: BRCA2 c.8414_8416delinsC (p.Leu2805SerfsX6) 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 326 control chromosomes. c.8414_8416delinsC has been reported in the literature in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome and prostate cancer (example, Rebbeck_2018, Waisbren_2015). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six clinical diagnostic laboratories and one expert panel (ENIGMA) have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
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