rs1060502772
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Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_024675.4(PALB2):c.932_933insC(p.Lys311fs) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,686 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 6.8e-7 ( 0 hom. )
Consequence
PALB2
NM_024675.4 frameshift
NM_024675.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 0.0100
Genes affected
PALB2 (HGNC:26144): (partner and localizer of BRCA2) This gene encodes a protein that may function in tumor suppression. This protein binds to and colocalizes with the breast cancer 2 early onset protein (BRCA2) in nuclear foci and likely permits the stable intranuclear localization and accumulation of BRCA2. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 16-23635613-T-TG is Pathogenic according to our data. Variant chr16-23635613-T-TG is described in ClinVar as [Pathogenic]. Clinvar id is 410166.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
PALB2 | NM_024675.4 | c.932_933insC | p.Lys311fs | frameshift_variant | 4/13 | ENST00000261584.9 | NP_078951.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
PALB2 | ENST00000261584.9 | c.932_933insC | p.Lys311fs | frameshift_variant | 4/13 | 1 | NM_024675.4 | ENSP00000261584.4 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
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32
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461686Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 727126
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GnomAD4 genome Cov.: 32
GnomAD4 genome
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32
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:7
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Hereditary cancer-predisposing syndrome Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Aug 31, 2021 | This variant inserts 1 nucleotide in exon 4 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. To our knowledge, this variant has not been reported in individuals affected with hereditary cancer in the literature. 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. - |
Pathogenic, no assertion criteria provided | research | Center of Medical Genetics and Primary Health Care | Apr 08, 2020 | The PALB2 variant p.Lys311Asnfs is a frameshift variant located in exon 4 and the BRCA1 interaction functional domain. It is expected to result in an absent or disrupted protein product and loss-of-function variants in PALB2 are known to be pathogenic (PMID: 17200668, 24136930, 25099575) (PVS1 Pathogenic Very Strong). It is in a mutation hotspot in a vicinity of 8 pathogenic variants (PM1 Pathogenic Moderate). This variant is not found in GnomAD exomes neither in GnomAD genomes (PM2 Pathogenic Moderate). This variant is reported in ClinVar as a pathogenic variant. In our study this variant was found in a 68-year-old female with a family history of cancer. Particularly, her brother was diagnosed with prostate cancer at age 62. Therefore, based on the evidence, we classified this variant as a Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | May 17, 2024 | The c.932_933insC pathogenic mutation, located in coding exon 4 of the PALB2 gene, results from an insertion of one nucleotide at position 932, causing a translational frameshift with a predicted alternate stop codon (p.K311Nfs*10). 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:2
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Feb 26, 2023 | For these reasons, this variant has been classified as Pathogenic. This sequence change creates a premature translational stop signal (p.Lys311Asnfs*10) 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: 410166). - |
Pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Sep 07, 2023 | This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation. - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Aug 30, 2022 | 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); This variant is associated with the following publications: (PMID: 24136930, 17200668, 33558524, 25099575, 32658311) - |
Breast carcinoma Pathogenic:1
Likely pathogenic, no assertion criteria provided | clinical testing | Medical Genetics Laboratory, Umraniye Training and Research Hospital, University of Health Sciences | Aug 09, 2021 | - - |
Computational scores
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at