chr16-23636122-T-A
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong
The NM_024675.4(PALB2):c.424A>T(p.Lys142Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000744 in 1,613,488 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. K142K) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_024675.4 stop_gained
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.424A>T | p.Lys142Ter | stop_gained | 4/13 | ENST00000261584.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PALB2 | ENST00000261584.9 | c.424A>T | p.Lys142Ter | stop_gained | 4/13 | 1 | NM_024675.4 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000132 AC: 2AN: 151850Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000796 AC: 2AN: 251270Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135790
GnomAD4 exome AF: 0.00000684 AC: 10AN: 1461638Hom.: 0 Cov.: 32 AF XY: 0.00000688 AC XY: 5AN XY: 727108
GnomAD4 genome AF: 0.0000132 AC: 2AN: 151850Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74166
ClinVar
Submissions by phenotype
Familial cancer of breast Pathogenic:4
Pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Feb 06, 2018 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Mar 31, 2023 | This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation. - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Jan 17, 2024 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 13, 2024 | This sequence change creates a premature translational stop signal (p.Lys142*) 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 (rs587782005, gnomAD 0.002%). This premature translational stop signal has been observed in individual(s) with breast cancer (PMID: 28779002). ClinVar contains an entry for this variant (Variation ID: 141779). For these reasons, this variant has been classified as Pathogenic. - |
Hereditary cancer-predisposing syndrome Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Apr 22, 2022 | The p.K142* pathogenic mutation (also known as c.424A>T), located in coding exon 4 of the PALB2 gene, results from an A to T substitution at nucleotide position 424. This changes the amino acid from a lysine to a stop codon within coding exon 4. This mutation was identified in a cohort of breast cancer patients from the UK and was not present in controls (Decker B et al. J. Med. Genet. 2017 Nov;54:732-741). 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 | Mar 09, 2022 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Jul 16, 2017 | - - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Sep 22, 2023 | Nonsense variant predicted to result in protein truncation and 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; This variant is associated with the following publications: (PMID: 28152038, 28779002, 29922827, 26689913, 29625052, 17200672, 17200671, 17200668, 25099575, 35753512, 33471991, 30322717, 24136930, 32885271) - |
Pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Feb 24, 2022 | The PALB2 c.424A>T; p.Lys142Ter variant (rs587782005) is reported in the literature in individuals affected with breast or ovarian cancer (Carter 2018, Decker 2017, Huang 2018). This variant is also reported in ClinVar (Variation ID: 141779), but is only observed on two alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. This variant induces an early termination codon and is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered to be pathogenic. References: Carter NJ et al. Germline pathogenic variants identified in women with ovarian tumors. Gynecol Oncol. 2018 Dec;151(3):481-488. PMID: 30322717. Decker B et al. Rare, protein-truncating variants in ATM, CHEK2 and PALB2, but not XRCC2, are associated with increased breast cancer risks. J Med Genet. 2017 Nov;54(11):732-741. PMID: 28779002. Huang KL et al. Pathogenic Germline Variants in 10,389 Adult Cancers. Cell. 2018 Apr 5;173(2):355-370.e14. PMID: 29625052. - |
Malignant tumor of breast Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Dec 17, 2021 | Variant summary: PALB2 c.424A>T (p.Lys142X) 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. The variant allele was found at a frequency of 8e-06 in 251270 control chromosomes (gnomAD). c.424A>T has been reported in the literature in individuals affected with breast cancer and ovarian cancer (e.g. Decker_2017, Carter_2018, Huang_2018). These data indicate that the variant is likely to be associated with disease. Five ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Pathogenic, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The PALB2 p.Lys142X variant was not identified in the literature nor was it identified in the COSMIC, MutDB, LOVD 3.0, or Zhejiang Colon Cancer databases. The variant was identified in dbSNP (ID: rs587782005) as “With Pathogenic allele”, and in the ClinVar and Clinvitae databases (3x classified as pathogenic by Ambry Genetics, GeneDx and Invitae). The variant was identified in control databases in 2 of 246078 chromosomes at a frequency of 0.000008 (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include European (Non-Finnish) in 2 of 111646 chromosomes (freq: 0.000018), while the variant was not observed in the African, Ashkenazi Jewish, East Asian, European (Finnish), Latino, Other, and South Asian populations. The c.424A>T variant leads to a premature stop codon at position 142 which is predicted to result in a truncated or absent protein and loss of function. Loss of function variants of the PALB2 gene are an established mechanism of disease in breast cancer and is the type of variant expected to cause the disorder. In summary, based on the above information this variant meets our laboratory’s criteria to be classified as pathogenic. - |
PALB2-related disorder Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center | Sep 11, 2023 | PVS1, PS4, PM2 - |
Breast cancer, susceptibility to Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | National Institute of Allergy and Infectious Diseases - Centralized Sequencing Program, National Institutes of Health | Aug 06, 2021 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at