chr13-32398608-C-CT
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PVS1_ModerateBP6
The NM_000059.4(BRCA2):c.10095_10096insT(p.Ser3366Ter) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000311 in 1,614,162 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. V3365VNYI?) has been classified as Likely benign.
Frequency
Consequence
NM_000059.4 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 1 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
BRCA2 | NM_000059.4 | c.10095_10096insT | p.Ser3366Ter | frameshift_variant | 27/27 | ENST00000380152.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
BRCA2 | ENST00000380152.8 | c.10095_10096insT | p.Ser3366Ter | frameshift_variant | 27/27 | 5 | NM_000059.4 | A2 |
Frequencies
GnomAD3 genomes AF: 0.000296 AC: 45AN: 152194Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000207 AC: 52AN: 251160Hom.: 0 AF XY: 0.000206 AC XY: 28AN XY: 135746
GnomAD4 exome AF: 0.000313 AC: 457AN: 1461850Hom.: 1 Cov.: 31 AF XY: 0.000323 AC XY: 235AN XY: 727222
GnomAD4 genome AF: 0.000295 AC: 45AN: 152312Hom.: 0 Cov.: 32 AF XY: 0.000295 AC XY: 22AN XY: 74484
ClinVar
Submissions by phenotype
Hereditary cancer-predisposing syndrome Benign:3
Likely benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Feb 22, 2017 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 03, 2020 | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
Likely benign, criteria provided, single submitter | curation | Sema4, Sema4 | Feb 17, 2021 | - - |
Hereditary breast ovarian cancer syndrome Uncertain:1Benign:1
Uncertain significance, no assertion criteria provided | clinical testing | Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C. | Dec 21, 2021 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Dec 06, 2023 | - - |
Breast-ovarian cancer, familial, susceptibility to, 2 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Centre for Mendelian Genomics, University Medical Centre Ljubljana | Feb 10, 2020 | This variant was classified as: Uncertain significance. The available evidence on this variant's pathogenicity is insufficient or conflicting. The following ACMG criteria were applied in classifying this variant: PVS1. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | May 08, 2019 | The p.Ser3366X variant in BRCA2 has not been previously reported in individuals with cancer, but has been identified in 40/66644 European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org). This nonsense variant leads to a premature termination codon at position 3366. This termination codon occurs within the last exon and is more likely to escape nonsense mediated decay (NMD) and result in a truncated protein. It is unclear if this will impact the protein function. In summary, the clinical significance of the p.Ser3366X variant is uncertain. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at