NM_000059.4:c.3554_3563delCAGTTGAAAT
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000059.4(BRCA2):c.3554_3563delCAGTTGAAAT(p.Thr1185IlefsTer9) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★★). Synonymous variant affecting the same amino acid position (i.e. T1185T) has been classified as Likely benign. 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.3554_3563delCAGTTGAAAT | p.Thr1185IlefsTer9 | frameshift_variant | Exon 11 of 27 | 5 | NM_000059.4 | ENSP00000369497.3 | ||
BRCA2 | ENST00000530893.7 | c.3185_3194delCAGTTGAAAT | p.Thr1062IlefsTer9 | frameshift_variant | Exon 11 of 27 | 1 | ENSP00000499438.2 | |||
BRCA2 | ENST00000614259.2 | n.3554_3563delCAGTTGAAAT | non_coding_transcript_exon_variant | Exon 10 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:1
Variant allele predicted to encode a truncated non-functional protein. -
not provided Pathogenic:1
This sequence change deletes 10 nucleotides from exon 11 of the BRCA2 mRNA causing a frameshift at codon 1185 and the creation of a premature translation stop signal 9 amino acid residues later. This is expected to result in an absent or disrupted protein product. This variant has been reported in the literature in a breast cancer patient (PMID: 22085629). The mutation database ClinVar contains entries for this variant (Variation ID: 51486). -
Hereditary cancer-predisposing syndrome Pathogenic:1
The c.3554_3563del10 pathogenic mutation, located in coding exon 10 of the BRCA2 gene, results from a deletion of 10 nucleotides at nucleotide positions 3554 to 3563, causing a translational frameshift with a predicted alternate stop codon (p.T1185Ifs*9). This mutation (also designated as 3782del10 and c.3554_3563delCAGTTGAAAT in published literature) has been reported in several cohorts of Greek breast cancer patients (Koumpis C et al. Hered Cancer Clin Pract, 2011 Nov;9:10; Apessos A et al. Cancer Genet, 2018 Jan;220:1-12; Fostira F et al. J Med Genet, 2020 Jan;57:53-61). 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:1
This sequence change creates a premature translational stop signal (p.Thr1185Ilefs*9) 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: 22085629). This variant is also known as c.3782del10. ClinVar contains an entry for this variant (Variation ID: 51486). For these reasons, this variant has been classified as Pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at