rs180177143
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong
The NM_024675.4(PALB2):c.172_175del(p.Gln60ArgfsTer7) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000217 in 1,613,858 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. L58L) 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.172_175del | p.Gln60ArgfsTer7 | frameshift_variant | 3/13 | ENST00000261584.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PALB2 | ENST00000261584.9 | c.172_175del | p.Gln60ArgfsTer7 | frameshift_variant | 3/13 | 1 | NM_024675.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000263 AC: 4AN: 152126Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000398 AC: 10AN: 251472Hom.: 0 AF XY: 0.0000368 AC XY: 5AN XY: 135908
GnomAD4 exome AF: 0.0000212 AC: 31AN: 1461732Hom.: 0 AF XY: 0.0000193 AC XY: 14AN XY: 727188
GnomAD4 genome ? AF: 0.0000263 AC: 4AN: 152126Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3AN XY: 74326
ClinVar
Submissions by phenotype
Familial cancer of breast Pathogenic:10
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 10, 2024 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | Mar 20, 2024 | Criteria applied: PVS1,PS4,PM5_SUP - |
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 | Invitae | Jan 28, 2024 | This sequence change creates a premature translational stop signal (p.Gln60Argfs*7) 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 (rs180177143, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with pancreatic cancer (PMID: 19264984, 21285249, 21618343, 22310028, 24136930, 25959805, 27038244, 27616075). ClinVar contains an entry for this variant (Variation ID: 126623). For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | research | Centre for Mendelian Genomics, University Medical Centre Ljubljana | Dec 09, 2022 | PVS1, PS4_STR - |
Likely pathogenic, criteria provided, single submitter | case-control | Cancer Genetics Laboratory, Peter MacCallum Cancer Centre | Jun 01, 2015 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Department of Molecular Diagnostics, Institute of Oncology Ljubljana | Apr 02, 2020 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | MGZ Medical Genetics Center | Jun 03, 2022 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Aug 15, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine | Apr 27, 2018 | A heterozygous c.172_17del (p.Gln60Argfs*7) pathogenic variant in the PALB2 gene was detected in this individual. This variant has been previously described as disease-causing in pancreatic, breast and ovarian cancer (PMID: 19264984, 27038244, 25959805, 21285249, 21285249, 22310028, 22310028). Therefore, we consider this variant to be pathogenic. - |
not provided Pathogenic:8
Pathogenic, criteria provided, single submitter | clinical testing | Clinical Genetics and Genomics, Karolinska University Hospital | Apr 26, 2019 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden | Nov 03, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Feb 01, 2024 | PALB2: PVS1, PS4, PS3:Supporting - |
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen | Oct 23, 2020 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Sep 17, 2019 | Recurrent variant in Polish and Czech populations (Janatova 2013, Cybulski 2015); 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; Case control studies suggest this variant is associated with breast and pancreatic cancer (Cybulski 2015, Lener 2016); Observed in individuals with a personal or family history consistent with pathogenic variants in this gene (Jones 2009, Casadei 2011, Hellebrand 2011, Janatova 2013, Thompson 2015, Kluska 2017, Kraus 2017); This variant is associated with the following publications: (PMID: 26283626, 22310028, 24136930, 30716324, 19264984, 21285249, 25330149, 25959805, 21618343, 27038244, 23935381, 24982446, 28008555, 27488870, 26843898, 27099641, 27616075, 23242139, 26681312, 27757719, 28279176, 28281021, 28454591, 28724667, 28657667, 25452441, 24549055, 29052111, 29753700, 30086788, 30426508, 30322717, 31159747, 30113427, 31312277, 31757951, 29625052, 26689913, 32052252, 31447099, 31948886, 32339256) - |
Pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Aug 09, 2021 | This frameshift variant causes the premature termination of PALB2 protein synthesis. In the published literature, this variant has been reported in individuals with breast and/or ovarian cancer, pancreatic cancer, prostate cancer, and medulloblastoma (PMID: 32339256 (2020), 31948886 (2020), 29753700 (2018), 29052111 (2018), 25452441 (2015), 24549055 (2014), and 19264984 (2009)). In addition, it has been reported in an individual with Fanconi Anemia, compound heterozygous with a PALB2 splice variant (PMID: 32052252 (2020)). Based on the available information, this variant is classified as pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Dec 09, 2016 | - - |
Pathogenic, no assertion criteria provided | curation | Leiden Open Variation Database | Feb 28, 2020 | Curators: Marc Tischkowitz, Arleen D. Auerbach. Submitters to LOVD: Alfons Meindl, Marc Tischkowitz. - |
Hereditary cancer-predisposing syndrome Pathogenic:4
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 22, 2022 | The c.172_175delTTGT (p.Q60Rfs*7) alteration, located in exon 3 (coding exon 3) of the PALB2 gene, consists of a deletion of 4 nucleotides from position 172 to 175, causing a translational frameshift with a predicted alternate stop codon after 7 amino acids. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. This alteration has been reported in pancreatic, breast, and ovarian cancer patients, including multiple individuals with family histories significant for PALB2-related cancers (Jones, 2009; Casadei, 2011; Prokofyeva, 2012; Janatova, 2013; Cybulski, 2015; Kluska, 2017; Myszka, 2018). It was also seen in a patient with medulloblastoma (Waszak, 2018). Based on the available evidence, this alteration is classified as pathogenic. - |
Pathogenic, criteria provided, single submitter | curation | Sema4, Sema4 | Apr 30, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Dec 21, 2022 | This variant deletes 4 nucleotides in exon 3 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 over 15 individuals affected with breast and/or ovarian cancer (PMID: 21285249, 21618343, 22310028, 24136930, 25099575, 25452441, 26283626, 27616075, 28724667, 29052111), 2 individuals affected with pancreatic cancer (PMID: 19264984, 27038244) and an individual affected with medulloblastoma (PMID: 29753700). This variant also has been reported in a breast cancer case-control study in 40/12529 cases and 10/4702 unaffected individuals (OR = 4.02, 95% CI 1.6 to 16.2) and a breast cancer case-control meta-analysis in 24/60466 cases and 9/53461 unaffected individuals (OR = 2.358, 95%CI 1.096 to 5.074) (PMID: 25959805, 33471991; Leiden Open Variation Database DB-ID PALB2_010002). This variant has been identified in 12/282872 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. - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneKor MSA | Jan 01, 2020 | This variation is a deletion of 4 nucleotides from exon 3 of the PALB2 mRNA, causing a frameshift after codon 60 and the creation of a premature translation stop signal 7 amino acid residues later p.(Gln60Argfs*7). This is expected to result in an absent or disrupted protein product. Truncating mutation in PALB2 gene are known to be pathogenic. The mutation database ClinVar contains multiple entries for this variant (Variation ID: 126623). - |
Pancreatic cancer, susceptibility to, 3 Pathogenic:2Other:1
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | Dec 14, 2023 | Criteria applied: PVS1,PS4 - |
risk factor, no assertion criteria provided | literature only | OMIM | Apr 10, 2009 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics Laboratory, University Hospital Schleswig-Holstein | Oct 18, 2021 | - - |
Hereditary breast ovarian cancer syndrome Pathogenic:2
Pathogenic, no assertion criteria provided | clinical testing | BRCAlab, Lund University | Aug 26, 2022 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jan 02, 2019 | Variant summary: PALB2 c.172_175delTTGT (p.Gln60ArgfsX7) 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. The variant allele was found at a frequency of 4e-05 in 277228 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in PALB2 causing Hereditary Breast and Ovarian Cancer (4e-05 vs 0.00016), allowing no conclusion about variant significance. c.172_175delTTGT has been reported in the literature in multiple individuals affected with Hereditary Breast and Ovarian Cancer (Hellebrand 2011, Casadei 2011 ,Kraus 2016) and pancreatic cancer (Jones 2009). These data indicate that the variant is very likely to be associated with disease. In addition, a case-control study found this variant to be present at a significantly higher frequency in breast cancer patients than in unaffected controls (OR=5.02; p=0.0016) (Cybulski 2015). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Ten 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 (9)/likely pathogenic(1). Based on the evidence outlined above, the variant was classified as pathogenic. - |
Familial cancer of breast;C1835817:Fanconi anemia complementation group N;C3150547:Pancreatic cancer, susceptibility to, 3 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Jan 11, 2022 | - - |
Fanconi anemia complementation group N Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Jun 13, 2019 | - - |
Breast and/or ovarian cancer Pathogenic:1
Pathogenic, no assertion criteria provided | clinical testing | CZECANCA consortium | Jun 11, 2019 | - - |
Colorectal cancer Pathogenic:1
Likely pathogenic, no assertion criteria provided | research | Division of Gastroenterology and Hepatology, Shanghai Institute of Digestive Disease, Shanghai Jiao Tong University School of Medicine. | Jul 19, 2021 | The Leu58fs variant in PALB2 has been reported in 1 Chinese family with autosomal dominant predisposition in familial colorectal cancer (CRC). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at