rs180177085
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_024675.4(PALB2):c.395del(p.Val132AlafsTer45) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,460,710 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. V132V) has been classified as Likely benign. 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
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PALB2 | NM_024675.4 | c.395del | p.Val132AlafsTer45 | frameshift_variant | 4/13 | ENST00000261584.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PALB2 | ENST00000261584.9 | c.395del | p.Val132AlafsTer45 | frameshift_variant | 4/13 | 1 | NM_024675.4 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 exomes AF: 0.00000798 AC: 2AN: 250634Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135436
GnomAD4 exome AF: 0.00000137 AC: 2AN: 1460710Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 726586
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Familial cancer of breast Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jun 07, 2020 | This variant has been reported in an individual affected with Fanconi anemia (PMID: 17200671). ClinVar contains an entry for this variant (Variation ID: 126748). This variant is present in population databases (rs180177085, ExAC 0.003%). This sequence change creates a premature translational stop signal (p.Val132Alafs*45) 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, 24136930, 25099575). For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Sep 06, 2023 | This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation. - |
Fanconi anemia complementation group N Pathogenic:1
Pathogenic, no assertion criteria provided | curation | Leiden Open Variation Database | May 13, 2019 | Curators: Marc Tischkowitz, Arleen D. Auerbach. Submitters to LOVD: Arleen D. Auerbach, LOVD-team, but with Curator vacancy, Marc Tischkowitz. - |
Hereditary cancer-predisposing syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 15, 2023 | The c.395delT pathogenic mutation, located in coding exon 4 of the PALB2 gene, results from a deletion of one nucleotide at nucleotide position 395, causing a translational frameshift with a predicted alternate stop codon (p.V132Afs*45). This mutation has been reported in trans with another PALB2 mutation in an individual with Fanconi anemia (Reid S et al. Nat. Genet. 2007 Feb;39(2):162-4). In addition to the clinical data presented in the literature, 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