chr16-23636043-G-GA
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_024675.4(PALB2):c.502dupT(p.Ser168PhefsTer17) 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 (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_024675.4 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome Cov.: 32
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
not provided Pathogenic:1
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; Has not been previously published as pathogenic or benign to our knowledge -
Hereditary cancer-predisposing syndrome Pathogenic:1
The c.502dupT pathogenic mutation, located in coding exon 4 of the PALB2 gene, results from a duplication of T at nucleotide position 502, causing a translational frameshift with a predicted alternate stop codon (p.S168Ffs*17). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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. -
Familial cancer of breast Pathogenic:1
This variant has not been reported in the literature in individuals with PALB2-related disease. This sequence change creates a premature translational stop signal (p.Ser168Phefs*17) in the PALB2 gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). Loss-of-function variants in PALB2 are known to be pathogenic (PMID: 17200668, 24136930, 25099575). 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