rs876659770
Variant summary
Our verdict is Pathogenic. Variant got 22 ACMG points: 22P and 0B. PVS1PS1PM2PP5_Very_Strong
The NM_000059.4(BRCA2):c.7209_7212delCAAAinsGG(p.Lys2404GlyfsTer7) variant causes a frameshift, missense change. 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. Synonymous variant affecting the same amino acid position (i.e. T2403T) has been classified as Likely benign. 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.7209_7212delCAAAinsGG | p.Lys2404GlyfsTer7 | frameshift_variant, missense_variant | Exon 14 of 27 | 5 | NM_000059.4 | ENSP00000369497.3 | ||
BRCA2 | ENST00000530893.7 | c.6840_6843delCAAAinsGG | p.Lys2281GlyfsTer7 | frameshift_variant, missense_variant | Exon 14 of 27 | 1 | ENSP00000499438.2 | |||
BRCA2 | ENST00000614259.2 | n.7209_7212delCAAAinsGG | non_coding_transcript_exon_variant | Exon 13 of 26 | 2 | ENSP00000506251.1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Breast-ovarian cancer, familial, susceptibility to, 2 Pathogenic:2
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Variant allele predicted to encode a truncated non-functional protein. -
Familial cancer of breast Pathogenic:1
This sequence change deletes 4 nucleotides and inserts 2 other nucleotides in exon 14 of the BRCA2 mRNA. This creates a premature translational stop signal 7 amino acid residues later and is expected to result in an absent or disrupted protein product. Truncating variants in BRCA2 are known to be pathogenic (PMID: 20104584). This variant has been described in the international literature in an individual with a personal and/or family history of breast cancer and/or ovarian cancer (PMID: 24156927) and in an individual undergoing panel testing for hereditary syndrome (PMID: 31159747). The mutation database ClinVar contains entries for this variant (Variation ID: 232446). -
Hereditary cancer-predisposing syndrome Pathogenic:1
The c.7209_7212delCAAAinsGG pathogenic mutation (also known as 7437delCAAAinsGG), located in coding exon 13 of the BRCA2 gene, results from the deletion of 4 nucleotides and insertion of two nucleotides causing a translational frameshift with a predicted alternate stop codon. This mutation has been reported in a high-risk breast and/or ovarian cancer patient in Austria (Tea MK et al. Maturitas. 2014 Jan;77(1):68-72).In addition to the clinical data presented in the literature, since frameshifts are typically deleterious in nature, this alteration is interpreted as a disease-causing mutation (ACMG Recommendations for Standards for Interpretation and Reporting of Sequence Variations. Revision 2007. Genet Med. 2008;10:294). -
Hereditary breast ovarian cancer syndrome Pathogenic:1
This sequence change creates a premature translational stop signal (p.Lys2404Glyfs*7) in the BRCA2 gene. It is expected to result in an absent or disrupted protein product. For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in BRCA2 are known to be pathogenic (PMID: 20104584). This variant has been reported in an individual with a personal and/or family history of breast cancer and/or ovarian cancer (PMID: 24156927). This variant is not present in population databases (ExAC no frequency). -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at