NM_024675.4:c.1675_1676delCAinsTG
Variant summary
Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong
The NM_024675.4(PALB2):c.1675_1676delCAinsTG(p.Gln559*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. The variant is present in control chromosomes in GnomAd MNV project. The variant allele was found at a frequency of 0.000008 in 2 alleles, including 0 homozygotes. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position has been classified as Pathogenic. Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_024675.4 stop_gained
Scores
Clinical Significance
Conservation
Publications
- hereditary breast carcinomaInheritance: AD Classification: DEFINITIVE Submitted by: ClinGen, Ambry Genetics
- Fanconi anemia complementation group NInheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics
- pancreatic cancer, susceptibility to, 3Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
- familial ovarian cancerInheritance: AD Classification: MODERATE Submitted by: ClinGen
- Fanconi anemiaInheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
- hereditary nonpolyposis colon cancerInheritance: AD Classification: LIMITED Submitted by: ClinGen
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ACMG classification
Our verdict: Pathogenic. The variant received 16 ACMG points.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| PALB2 | NM_024675.4 | c.1675_1676delCAinsTG | p.Gln559* | stop_gained | ENST00000261584.9 | NP_078951.2 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| PALB2 | ENST00000261584.9 | c.1675_1676delCAinsTG | p.Gln559* | stop_gained | 1 | NM_024675.4 | ENSP00000261584.4 |
Frequencies
GnomAD3 genomes
GnomAD4 genome
ClinVar
Submissions by phenotype
not provided Pathogenic:2
This variant causes the premature termination of PALB2 protein synthesis. In the published literature, this variant has been reported in individuals with breast cancer (PMID: 26681312 (2015)) and pancreatic cancer (PMID: 33413558 (2021)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Based on the available information, this variant is classified as pathogenic. -
Observed in individuals with a personal or family history consistent with pathogenic variants in this gene (Bonache et al., 2018; Momozawa et al., 2018; Abe et al., 2021; Botrus et al., 2022); Nonsense 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); 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: 26681312, 28152038, 30287823, 30306255, 30792206, 31589614, 33413558, 35238112, 36359225) -
Familial cancer of breast Pathogenic:2
This sequence change creates a premature translational stop signal (p.Gln559*) 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). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individual(s) with breast cancer (PMID: 26681312). ClinVar contains an entry for this variant (Variation ID: 128121). For these reasons, this variant has been classified as Pathogenic. -
This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation. -
Hereditary cancer-predisposing syndrome Pathogenic:2
The c.1675_1676delCAinsTG pathogenic mutation, located in coding exon 4 of the PALB2 gene, results from an in-frame deletion of CA and insertion of TG at nucleotide positions 1675 and 1676. This changes the glutamine at codon 559 to a stop codon (p.Q559*). This mutation was identified in a breast cancer proband from a cohort of 10030 consecutive patients referred for evaluation by an NGS hereditary cancer panel (Susswein LR et al. Genet. Med. 2016 08;18(8):823-32). 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. -
This variant changes 1 nucleotide in exon 4 of the PALB2 gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in an individual with breast cancer (PMID: 26681312) and in an individual with familial pancreatic cancer (PMID: 33413558). 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. -
Familial cancer of breast;C1835817:Fanconi anemia complementation group N;C3150547:Pancreatic cancer, susceptibility to, 3 Pathogenic:1
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PALB2-related disorder Pathogenic:1
The PALB2 c.1675_1676delinsTG variant is predicted to result in premature protein termination (p.Gln559*). This variant has been reported in multiple large cancer studies (see example: Table S1, Susswein et al. 2016. PubMed ID: 26681312; Abe et al. 2021. PubMed ID: 33413558). This variant is not present in a large population database and is reported as pathogenic in the ClinVar database (https://preview.ncbi.nlm.nih.gov/clinvar/variation/128121/). Nonsense variants in PALB2 are expected to be pathogenic. Given all the evidence, we interpret c.1675_1676delinsTG (p.Gln559*) as pathogenic. -
Precursor B-cell acute lymphoblastic leukemia Pathogenic:1
This is a nonsense alteration in which coding positions 1675 and 1676 are deleted and replaced by TG. This alteration is predicted to change a Glutamine to a premature stop codon at amino acid codon 559. Classification criteria: PVS1, PS3, PM2. -
Malignant tumor of breast Pathogenic:1
Variant summary: PALB2 c.1675_1676delinsTG (p.Gln559X) 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 250092 control chromosomes. c.1675_1676delinsTG has been reported in the literature in at least one individual affected with Breast Cancer (e.g. Susswein_2016). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories 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