rs876658170
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_024675.4(PALB2):c.2296_2297delTC(p.Val767LeufsTer5) 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 genome Cov.: 32
ClinVar
Submissions by phenotype
not provided Pathogenic:2
PALB2: PVS1, PM2, PS4:Moderate -
This deletion of 2 nucleotides in PALB2 is denoted c.2296_2297delTC at the cDNA level and p.Val767LeufsX5 (V767LfsX5) at the protein level. The normal sequence, with the bases that are deleted in brackets, is AGAC[delTC]AGTC. The deletion causes a frameshift which changes a Valine to a Leucine at codon 767, and creates a premature stop codon at position 5 of the new reading frame. Although this variant has not, to our knowledge, been reported in the literature, it is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay, and is considered to be pathogenic. -
Familial cancer of breast Pathogenic:2
This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation. -
This sequence change creates a premature translational stop signal (p.Val767Leufs*5) in the PALB2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PALB2 are known to be pathogenic (PMID: 17200668, 17200671, 17200672, 24136930, 25099575). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with PALB2-related conditions. ClinVar contains an entry for this variant (Variation ID: 229748). For these reasons, this variant has been classified as Pathogenic. -
Hereditary cancer-predisposing syndrome Pathogenic:1
The c.2296_2297delTC pathogenic mutation, located in coding exon 5 of the PALB2 gene, results from a deletion of two nucleotides at nucleotide positions 2296 to 2297, causing a translational frameshift with a predicted alternate stop codon (p.V767Lfs*5). 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. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at