chr16-23629862-TTTCA-T
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_024675.4(PALB2):c.2288_2291delTGAA(p.Leu763fs) 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 Likely 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
GnomAD4 genome
ClinVar
Submissions by phenotype
Familial cancer of breast Pathogenic:5
This sequence change creates a premature translational stop signal (p.Leu763*) 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: 232125). For these reasons, this variant has been classified as Pathogenic. -
Variant summary: PALB2 c.2288_2291delTGAA (p.Leu763X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g. c.2920_2921delAA (p.Lys974fsX5), c.3113G>A (p.Trp1038X), c.3323delA (p.Tyr1108fsX16)). The variant was absent in 246264 control chromosomes. To our knowledge, no occurrence of c.2288_2291delTGAA in individuals affected with Hereditary Breast and Ovarian Cancer and no experimental evidence demonstrating its impact on protein function have been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. -
This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation. -
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Hereditary cancer-predisposing syndrome Pathogenic:3
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The c.2288_2291delTGAA pathogenic mutation, located in coding exon 5 of the PALB2 gene, results from a deletion of 4 nucleotides at nucleotide positions 2288 to 2291, causing a translational frameshift with a predicted alternate stop codon (p.L763*). 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. -
This variant deletes 4 nucleotides in exon 5 of the PALB2 gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in one individual with hereditary breast and ovarian cancer syndrome (PMID: 31921681). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of PALB2 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. -
not provided Pathogenic:2
This nonsense variant causes the premature termination of PALB2 protein synthesis. It has been reported in at least one individual with hereditary breast and/or ovarian cancer in the published literature (PMID: 31921681 (2019)). Therefore, the variant is classified as pathogenic. -
Nonsense 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; Observed in individuals with breast and/or ovarian cancer as well as other cancers (PMID: 31921681, 32885271); This variant is associated with the following publications: (PMID: 33471991, 17200672, 24136930, 28569743, 17200671, 25099575, 17200668, 32885271, 35867948, 31921681) -
Pancreatic cancer, susceptibility to, 3 Pathogenic:1
The PALB2 p.Leu763* variant was not identified in the literature nor was it identified in the Cosmic, MutDB, LOVD 3.0, or Zhejiang University databases. The variant was identified in dbSNP (ID: rs876659571) as "With Pathogenic allele", and in ClinVar (classified as pathogenic by Ambry Genetics, GeneDx, Invitae and Color Genomics; as likely pathogenic by Counsyl). The variant was not identified in the following control databases: the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). The c.2288_2291del variant leads to a premature stop codon at position 763 which is predicted to lead to a truncated or absent protein and loss of function. Loss of function variants of the PALB2 gene are an established mechanism of disease in PALB2-associated cancer and is the type of variant expected to cause the disorder. The variant occurs outside of the splicing consensus sequence and 1 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, GeneSplicer) predict a greater than 10% difference in splicing. In summary, based on the above information this variant meets our laboratory’s criteria to be classified as pathogenic. -
Breast-ovarian cancer, familial, susceptibility to, 5 Pathogenic:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at