16-23636035-ATC-A
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong
The NM_024675.4(PALB2):c.509_510delGA(p.Arg170IlefsTer14) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000186 in 1,614,006 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). 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
Ensembl
Frequencies
GnomAD3 genomes 0.0000131 AC: 2AN: 152126Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000358 AC: 9AN: 251446Hom.: 0 AF XY: 0.0000294 AC XY: 4AN XY: 135892
GnomAD4 exome AF: 0.0000192 AC: 28AN: 1461880Hom.: 0 AF XY: 0.0000179 AC XY: 13AN XY: 727240
GnomAD4 genome 0.0000131 AC: 2AN: 152126Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74310
ClinVar
Submissions by phenotype
not provided Pathogenic:14
Curators: Marc Tischkowitz, Arleen D. Auerbach. Submitters to LOVD: Andreas Laner, Marc Tischkowitz. -
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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; Observed in individuals with breast and pancreatic cancers and is a recurrent pathogenic variant in Central and Eastern European populations (Dansonka-Mieszkowska 2010, Slater 2010, Casadei 2011, Noskowicz 2014, Cybulski 2015, Wojcik 2016, Kluska 2017, Hilz 2019); Case control studies suggest this variant is associated with breast cancer (Cybulski 2015); Not observed at a significant frequency in large population cohorts (Lek 2016); This variant is associated with the following publications: (PMID: 28407996, 26720728, 23935381, 20122277, 20412113, 21285249, 26843898, 24061862, 27038244, 28279176, 28709830, 27488870, 27757719, 27624329, 27099641, 27106063, 25330149, 26270727, 20582465, 28158555, 25959805, 29478780, 29052111, 30086788, 30833416, 31159747, 30113427, 31312277, 31570822, 29625052, 26689913, 32885271, 32554798) -
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This frameshift variant causes the premature termination of PALB2 protein synthesis. In addition, it has been identified in individuals with breast, ovarian and pancreatic cancers as well as in healthy controls in the published literature (PMID: 28279176 (2017), 27106063 (2016), 27038244 (2016), 26720728 (2016), 26270727 (2015), 26083025 (2015), 25959805 (2015), 25452441 (2015), 25330149 (2015), 25186627 (2015), 25099575 (2014), 24415441 (2014), 24136930 (2013), 24061862 (2014), 21285249 (2011), 21165770 (2011), 20582465 (2011), 20412113 (2010), 20122277 (2010)). Functional studies in the published literature report this variant reduced DNA binding and failed to stimulate RAD51-mediated strand invasion (PMID: 28158555 (2017)). Based on the available information, this variant is classified as pathogenic. -
This pathogenic sequence change results in an amino acid frameshift and creates a premature stop codon 13 amino acids downstream of the mutation, p.Arg170Ilefs*14. This pathogenic sequence change is predicted to result in an abnormal transcript, which may be degraded, or may lead to the production of a truncated PALB2 protein with potentially abnormal function. This pathogenic sequence change has previously been described in patients with PALB2-related breast, ovarian and pancreatic cancers (Dansonka-Mieszkowska et al. 2010; Slater et al. 2010; Casadei et al. 2011; Bogdanova et al. 2011; Adank et al. 2011; Noskowicz et al. 2014; Kluska et al. 2017). Additionally, a breast cancer patient with t-MN was reported to have a different pathogenic PALB2 mutation (Churpek et al. 2016). This pathogenic sequence change may be the germline predisposition to this patient's therapy-related myeloid neoplasm (t-NM), however functional studies have not been performed to prove this conclusively. Compound heterozygous pathogenic variants in PALB2 have been associated with Fanconi anemia of complementation group N [OMIM#610832]. Heterozygous pathogenic variants in PALB2 have been associated with increased susceptibility to cancers including breast cancer [OMIM#114480] and pancreatic cancer [OMIM#613348]. -
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Familial cancer of breast Pathogenic:11
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This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation. -
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The p.Arg170IlefsX14 variant in PALB2 has been reported in numerous individuals with PABL2-associated cancers, including familial breast, ovarian, and pancreatic cancer and is considered to be a founder variant of central and eastern European origin (selected references: Dansonka-Mieszkowska 2010 PMID: 20122277, Slater 2010 PMID: 20412113, Casadei 2011 PMID: 21285249, Noskowicz 2014 PMID: 24061862, Cybulski 2015 PMID: 25330149, Kluska 2017 PMID: 28279176). This variant has also been reported by other clinical laboratories in ClinVar (Variation ID 126757) and has been identified in 0.001% (2/68010) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org, v.3.1). This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 170 and leads to a premature termination codon 14 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. 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: PVS1, PS4, PM2_Supporting. -
This sequence change creates a premature translational stop signal (p.Arg170Ilefs*14) 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 (rs515726124, gnomAD 0.007%). This premature translational stop signal has been observed in individual(s) with breast, ovarian, and pancreatic cancer (PMID: 20122277, 20412113, 21285249, 24061862, 25330149, 25959805, 26083025, 27038244, 27106063). ClinVar contains an entry for this variant (Variation ID: 126757). For these reasons, this variant has been classified as Pathogenic. -
Criteria applied: PVS1,PS4 -
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PVS1, PS3, PS4_STR -
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Hereditary cancer-predisposing syndrome Pathogenic:7
This variant deletes 2 nucleotides 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. A functional study reported that this variant impacts PALB2 binding to DNA (PMID: 28158555). This variant has been detected in over 40 individuals affected with breast, ovarian and pancreatic cancer (PMID: 20122277, 20412113, 20582465, 21285249, 24136930, 24061862, 25099575, 25186627, 26270727, 27106063, 33471991; Leiden Open Variation Database DB-ID PALB2_010036). This variant has been identified in 9/251446 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. -
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PVS1; PM5_SUP; PS4_SUP -
The c.509_510delGA pathogenic mutation, located in coding exon 4 of the PALB2 gene, results from a deletion of two nucleotides at nucleotide positions 509 to 510, causing a translational frameshift with a predicted alternate stop codon (p.R170Ifs*14). This alteration has been reported in familial breast, ovarian, and pancreatic cancer cohorts with carrier ethnicity data supporting c.509_510delGA as a founder mutation of central European origin (Dansonka-Mieszkowska A et al. BMC Med. Genet. 2010 Feb;11:20; Slater EP et al. Clin. Genet. 2010 Nov;78:490-4; Casadei S et al. Cancer Res. 2011 Mar;71:2222-9; Noskowicz M et al. Fam. Cancer. 2014 Jun;13:137-42; Cybulski C et al. Clin. Genet. 2015 Oct;88:366-70; Desmond A et al. JAMA Oncol. 2015 Oct;1:943-51; Kluska A et al. BMC Med. Genomics. 2017 Mar;10:14). Additional data has led authors to suggest that this is one of two PALB2 founder mutations associated with poor outcome in Polish breast cancer patients (Cybulski C et al. Lancet Oncol. 2015 Jun;16:638-44). Further, a functional characterization of this alteration showed that the truncated protein results in weakly bound DNA substrates, suggesting that the loss of the second DNA binding domain affects the affinity for DNA, resulting in significantly impaired DNA binding (Pauty J et al. Nucleic Acids Res. 2017 Mar;45:2644-2657). 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. -
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This mutation is a 2 bp deletion at codon 509 of the PALB2 gene. It results in a frame-shift creating new stop codon 14 amino acid residues later, thus resulting in absent or disrupted protein product. Truncating variants in PALB2 are known to be pathogenic. This particular truncation has been reported in the literature in association with familial breast and pancreatic cancers (PMID: 20412113; PMID: 21285249). The mutation database ClinVar contains multiple entries for this variant (Variation ID: 126757). -
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Breast and/or ovarian cancer Pathogenic:2
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PALB2-related disorder Pathogenic:2
The PALB2 c.509_510delGA variant is predicted to result in a frameshift and premature protein termination (p.Arg170Ilefs*14). This variant has been reported in multiple unrelated individuals with breast and/or ovarian cancer (see for example - Dansonka-Mieszkowska et al. 2010. PubMed ID: 20122277; Casadei et al. 2011. PubMed ID: 21285249; Cybulski et al. 2015. PubMed ID: 25330149). This variant is reported in 0.0070% of alleles in individuals of European (non-Finnish) descent in gnomAD and is interpreted as pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/126757/). Frameshift variants in PALB2 are expected to be pathogenic. This variant is interpreted as pathogenic. -
The PALB2 c.509_510delGA (p.Arg170IlefsTer14) variant results in frameshift and is predicted to result in premature truncation of the protein. The p.Arg170IlefsTer14 variant is reported in at least six studies in which it is found in a heterozygous state in a total of 23 breast cancer patients, two ovarian cancer patients and one pancreatic cancer patient (Dansonka-Mieszkowska et al. 2010; Slater et al. 2010; Casadei et al. 2011; Bogdanova et al. 2011; Adank et al. 2011; Noskowicz et al. 2014). This variant has not been reported in individuals with Fanconi anemia. The p.Arg170IlefsTer14 variant was found in a heterozygous state in one of 5097 controls and is reported at a frequency of 0.00010 in the European (non-Finnish) population of the Exome Aggregation Consortium. The variant creates a premature stop codon which shortens the PALB2 protein to 182 amino acids from 1186 amino acids. This removes the C-terminal domain which contains the WD40 repeats necessary for BRCA2/PALB2 complex formation. Other deletion variants that remove the C-terminal domain of the PALB2 protein have been shown to have highly reduced BRCA2 binding capacity and be defective in the repair of ds breaks and mitomyocin C-induced damages. To date, all PALB2 variants detected in families with breast cancer or Fanconi anemia have been frameshift or nonsense changes leading to a truncated protein. Based on the evidence and the potential impact of frameshift variants, the p.Arg170IlefsTer14 variant is classified as pathogenic for PALB2-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Malignant tumor of breast Pathogenic:2
The PALB2 p.Arg170Ilefs*14 variant was identified in 40 of 17778 proband chromosomes (frequency: 0.002) from American and Central European individuals or families with breast/ovarian cancer, colon or familial pancreatic cancer and was identified in 1 of 13574 control chromosomes (freq: 0.00007) from healthy individuals (Antoniou 2014 , AlDubayan 2018, Bogdanova 2011, Cybulski 2015, Dansonka-Mieszkowska 2010, Kluska 2017, Noskowicz 2014, Slater 2010). The variant was identified in dbSNP (ID: rs515726124) as "With Pathogenic allele", in ClinVar (classified pathogenic by GeneDx, Invitae, Ambry Genetics and 9 other submitters), and LOVD 3.0 (1x) databases. The variant was not identified in the following control databases: the 1000 Genomes Project, the NHLBI GO Exome Sequencing Project, the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). The c.509_510del variant is predicted to cause a frameshift, which alters the protein's amino acid sequence beginning at codon 170 and leads to a premature stop codon 14 codons downstream. This alteration is then 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 PALB2 associated 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. -
Variant summary: PALB2 c.509_510delGA (p.Arg170IlefsX14) 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 6.1e-05 in 260850 control chromosomes (gnomAD and publications). This frequency is not higher than expected for a pathogenic variant in PALB2 causing Breast Cancer (6.1e-05 vs 0.00016), allowing no conclusion about variant significance. c.509_510delGA has been reported in the literature in multiple individuals affected with breast cancer, ovarian cancer and pancreatic cancer (e.g. Dansonka-Mieszkowska_2010, Casadei_2011, Noskowicz_2014, Cybulski_2015, Borecka_2016). These data indicate that the variant is very likely to be associated with disease. Experimental evidence evaluating an impact on protein function demonstrated the variant impairs DNA binding ability, fails to stimulate RAD51 and fails to localize to DNA damage sites (Pauty_2017). Nineteen ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:1
Criteria applied: PVS1,PS4 -
Carcinoma of pancreas Pathogenic:1
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Breast-ovarian cancer, familial, susceptibility to, 5 Pathogenic:1
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Hereditary breast ovarian cancer syndrome Pathogenic:1
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Breast carcinoma Pathogenic:1
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not specified Pathogenic:1
The PALB2 c.509_510delGA; p.Arg170fs variant (rs515726124) is a recurrent alteration in individuals with breast cancer (Casadel 2011, Cybulski 2015, Cybulski 2015b, Dansonka-Mieszkowska 2010, Kluska 2017, Noskowicz 2014), and is significantly enriched in affected individuals compared to the healthy population (Cybulski 2015). This variant is reported as pathogenic in ClinVar (Variation ID: 126757), and found in the general population with a low overall allele frequency of 0.003% (8/246222 alleles) in the Genome Aggregation Database. This variant causes a frameshift by deleting 2 nucleotides, so it 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 Casadel S et al. Contribution of inherited mutations in the BRCA2-interacting protein PALB2 to familial breast cancer. Cancer Res. 2011; 71(6):2222-9. Cybulski C et al. Clinical outcomes in women with breast cancer and a PALB2 mutation: a prospective cohort analysis. Lancet Oncol. 2015; 16(6):638-44. Cybulski C et al. Mutations predisposing to breast cancer in 12 candidate genes in breast cancer patients from Poland. Clin Genet. 2015b; 88(4):366-70. Dansonka-Mieszkowska A et al. A novel germline PALB2 deletion in Polish breast and ovarian cancer patients. BMC Med Genet. 2010; 11:20. Kluska A et al. PALB2 mutations in BRCA1/2-mutation negative breast and ovarian cancer patients from Poland. BMC Med Genomics. 2017; 10(1):14. Noskowicz M et al. Prevalence of PALB2 mutation c.509_510delGA in unselected breast cancer patients from Central and Eastern Europe. Fam Cancer. 2014; 13(2):137-42. -
Familial cancer of breast;C1835817:Fanconi anemia complementation group N;C3150547:Pancreatic cancer, susceptibility to, 3 Pathogenic:1
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Fanconi anemia complementation group N Pathogenic:1
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Pancreatic cancer, susceptibility to, 3;C3469522:Breast cancer, susceptibility to Pathogenic:1
This c.509_510delGA (p.Arg170Ilefs*14) variant in the PALB2 gene is predicted to introduce a premature translation termination codon. This variant has been reported in multiple unrelated patients affected with breast cancer (PMID 21285249, 24061862, 25330149, 26083025), ovarian cancer (PMID 21285249) and pancreatic cancer (PMID 27106063) and is extremely rare in general population. Therefore, the c.509_510delGA (p.Arg170Ilefs*14) variant in the PALB2 gene is classified as pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at