rs515726071
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong
The NM_024675.4(PALB2):c.1479del(p.Thr494LeufsTer67) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000372 in 1,614,048 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. P493P) 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 16 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PALB2 | NM_024675.4 | c.1479del | p.Thr494LeufsTer67 | frameshift_variant | 4/13 | ENST00000261584.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PALB2 | ENST00000261584.9 | c.1479del | p.Thr494LeufsTer67 | frameshift_variant | 4/13 | 1 | NM_024675.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000197 AC: 3AN: 152156Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000119 AC: 3AN: 251458Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135904
GnomAD4 exome AF: 0.00000205 AC: 3AN: 1461892Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1AN XY: 727246
GnomAD4 genome ? AF: 0.0000197 AC: 3AN: 152156Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74332
ClinVar
Submissions by phenotype
Familial cancer of breast Pathogenic:6
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Aug 28, 2022 | - - |
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 | Jan 18, 2024 | This sequence change creates a premature translational stop signal (p.Thr494Leufs*67) 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 present in population databases (rs515726071, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with breast cancer (PMID: 21932393, 26720728). ClinVar contains an entry for this variant (Variation ID: 126606). For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Apr 03, 2023 | This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation. - |
Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jun 01, 2022 | The p.Thr494LeufsX67 variant in PALB2 has been reported in at least 6 individuals with PALB2-associated cancers, including at least 3 with breast cancer and at least 3 with ovarian cancer (selected references: Zheng 2012 PMID: 21932393, Kanchi 2014 PMID: 24448499, Lu 2015 PMID: 26689913, Churpek 2015 PMID: 25428789, Norquist 2016 PMID: 26720728, Lu 2019 PMID: 30128536). It has also been reported by other clinical laboratories in ClinVar (Variation ID 126606) and has been identified in 0.007% (3/41430) of African chromosomes by gnomAD (http://gnomad.broadinstitute.org, v.3.1.2). This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 494 and leads to a premature termination codon 67 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Heterozygous loss of function of the PALB2 gene is an established disease mechanism in PALB2-associated cancers, including autosomal dominant breast cancer. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant PALB2-associated cancers. ACMG/AMP Criteria applied: PM2_Supporting, PVS1, PS4_moderate. - |
Pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Jun 01, 2016 | - - |
Hereditary cancer-predisposing syndrome Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 07, 2022 | The c.1479delC pathogenic mutation, located in coding exon 4 of the PALB2 gene, results from a deletion of one nucleotide at nucleotide position 1479, causing a translational frameshift with a predicted alternate stop codon (p.T494Lfs*67). This mutation has been reported in multiple breast, ovarian, and/or pancreatic cancer patients (Zheng Y et al. Cancer. 2012 Mar 1;118(5):1362-70; Churpek JE et al. Breast Cancer Res. Treat., 2015 Jan;149:31-9; Norquist BM et al. JAMA Oncol 2016 Apr;2(4):482-90; Hu C et al. JAMA, 2018 06;319:2401-2409; Lu HM et al. JAMA Oncol, 2019 01;5:51-57; Huang KL et al. Cell, 2018 04;173:355-370.e14). 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. - |
Pathogenic, criteria provided, single submitter | curation | Sema4, Sema4 | Jan 19, 2022 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Jun 14, 2021 | This variant deletes 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, functional studies have not been reported for this variant. This variant has been reported in individuals affected with breast or ovarian cancer (PMID: 21932393, 24448499, 27153395, 26720728, 30128536). This variant has been identified in 3/251458 chromosomes 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:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jun 22, 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: 26689913, 29625052, 26720728, 24448499, 21932393, 30128536, 25428789, 34906458) - |
Hereditary breast ovarian cancer syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jul 26, 2019 | Variant summary: PALB2 c.1479delC (p.Thr494LeufsX67) 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.2167_2168delAT (p.Met723fsX21), c.2607delC (p.Val870X)). The variant allele was found at a frequency of 1.2e-05 in 251458 control chromosomes (gnomAD) and been reported in the literature in individuals affected with breast and ovarian cancer (Zheng_2012, Kanchi_2014, Norquist_2016, Lu_2018). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at