chr13-32362527-CTG-C
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000059.4(BRCA2):c.7815_7816del(p.Cys2605Ter) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,344 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★★). Synonymous variant affecting the same amino acid position (i.e. L2604L) 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
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
BRCA2 | NM_000059.4 | c.7815_7816del | p.Cys2605Ter | frameshift_variant | 17/27 | ENST00000380152.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BRCA2 | ENST00000380152.8 | c.7815_7816del | p.Cys2605Ter | frameshift_variant | 17/27 | 5 | NM_000059.4 | A2 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461344Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 727018
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Breast-ovarian cancer, familial, susceptibility to, 2 Pathogenic:2
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, reviewed by expert panel | curation | Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) | Oct 18, 2016 | Variant allele predicted to encode a truncated non-functional protein. - |
Hereditary cancer-predisposing syndrome Pathogenic:2
Pathogenic, criteria provided, single submitter | curation | Sema4, Sema4 | Feb 03, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 17, 2020 | The c.7815_7816delTG pathogenic mutation, located in coding exon 16 of the BRCA2 gene, results from a deletion of two nucleotides at nucleotide positions 7815 to 7816, causing a translational frameshift with a predicted alternate stop codon (p.C2605*). This mutation was identified in a Spanish individual that was part of a large, worldwide study of BRCA1/2 mutation positive families (Rebbeck TR et al. Hum. Mutat., 2018 05;39:593-620). Another BRCA2 alteration, c.7815T>A, that leads to the same premature stop codon (p.C2605*), was identified in 2/2991 Chinese breast cancer patients and was not detected in 1043 healthy controls (Lang GT et al. Int. J. Cancer, 2017 07;141:129-142). 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. - |
not provided Pathogenic:1
Pathogenic, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The p.Cys2605X variant has not been reported in the literature. The variant leads to a premature stop codon at position 2605 which is predicted to cause premature truncation of the protein product and loss of function. Loss of function variants in the BRCA2 gene is an established disease mechanism in hereditary breast and ovarian cancer. In summary, based on the above information, this variant is classified as pathogenic. - |
Hereditary breast ovarian cancer syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Aug 09, 2021 | 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 individuals in the Leiden Open-source Variation Database (PMID: 21520333). ClinVar contains an entry for this variant (Variation ID: 267037). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Cys2605*) in the BRCA2 gene. It is expected to result in an absent or disrupted protein product. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at