16-23637904-CT-C
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_024675.4(PALB2):βc.156delβ(p.Glu53LysfsTer15) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000658 in 152,038 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (β β ). Synonymous variant affecting the same amino acid position (i.e. V52V) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_024675.4 frameshift
Scores
Clinical Significance
Conservation
Genome browser will be placed here
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.156del | p.Glu53LysfsTer15 | frameshift_variant | 3/13 | ENST00000261584.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PALB2 | ENST00000261584.9 | c.156del | p.Glu53LysfsTer15 | frameshift_variant | 3/13 | 1 | NM_024675.4 | P1 |
Frequencies
GnomAD3 genomes AF: 0.00000658 AC: 1AN: 152038Hom.: 0 Cov.: 32
GnomAD4 exome Cov.: 31
GnomAD4 genome AF: 0.00000658 AC: 1AN: 152038Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74266
ClinVar
Submissions by phenotype
Familial cancer of breast Pathogenic:4
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. - |
Pathogenic, no assertion criteria provided | curation | Leiden Open Variation Database | May 13, 2019 | Curators: Marc Tischkowitz, Arleen D. Auerbach. Submitter to LOVD: Marc Tischkowitz. - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Sep 06, 2023 | This sequence change creates a premature translational stop signal (p.Glu53Lysfs*15) 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 premature translational stop signal has been observed in individual(s) with a personal and/or family history of breast cancer (PMID: 25099575, 25452441). ClinVar contains an entry for this variant (Variation ID: 143963). For these reasons, this variant has been classified as Pathogenic. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Feb 02, 2023 | - - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Feb 13, 2015 | This deletion of one nucleotide in PALB2 is denoted c.156delA at the cDNA level and p.Glu53LysfsX15 (E53KfsX15) at the protein level. The normal sequence, with the base that is deleted in brackets, is CAGT[A]GAAG. The deletion causes a frameshift, which changes a Glutamic Acid to a Lysine at codon 53, and creates a premature stop codon at position 15 of the new reading frame. This variant is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. PALB2 c.156delA has been published as a mutation, observed in a family with at least one case of breast cancer (Antoniou 2014). we consider this variant to be pathogenic. - |
Pathogenic, no assertion criteria provided | literature only | SNPedia | - | - - |
Hereditary cancer-predisposing syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 11, 2024 | The c.156delA pathogenic mutation, located in coding exon 3 of the PALB2 gene, results from a deletion of one nucleotide at nucleotide position 156, causing a translational frameshift with a predicted alternate stop codon (p.E53Kfs*15). This alteration was reported in one individual from a cohort of 1824 patients with triple negative breast cancer, unselected for family history or age of onset (Couch FJ et al. J. Clin. Oncol. 2015 Feb; 33(4):304-11). 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