16-23603471-G-T
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP1_StrongPM3_Strong
This summary comes from the ClinGen Evidence Repository: The c.3549C>A (p.Tyr1183Ter) variant in PALB2 is a nonsense variant that may cause a premature stop codon that is predicted to escape nonsense mediated decay, however it is a truncation of a functionally important region (removes amino acids 1183-1186) in a gene where loss-of-function is an established disease mechanism. This variant, or another variant leading to the same protein truncation, has been detected in three individuals with autosomal recessive FANCN. Of those individuals, three were compound heterozygous for the variant and a pathogenic or likely pathogenic variant and three of those were confirmed in trans by parental testing (co-occurring variants: c.2257C>T (p.Arg753Ter); c.2962C>T (p.Gln988Ter); c.3116delA (p.Asn1039Ilefs*2): PMID 17200671). The variant has been reported to segregate with breast and/or pancreatic cancer in 15 affected members from 6 families (Invitae; Ambry Genetics). This variant is non-functional in multiple different protein assays (PMID 31757951, PMID 31636395); however due to a lack of positive missense controls with known clinical impact, these protein assays do not meet the requirements for use by the HBOP VCEP. In summary, this variant meets the criteria to be classified as pathogenic for autosomal dominant hereditary breast and pancreatic cancer and autosomal recessive FANCN based on the ACMG/AMP criteria applied, as specified by the HBOP VCEP. (PVS1, PP1_Strong, PM3_Strong) LINK:https://erepo.genome.network/evrepo/ui/classification/CA288488/MONDO:0016419/020
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
Ensembl
Frequencies
GnomAD3 genomes
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251420Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135892
GnomAD4 exome AF: 0.00000342 AC: 5AN: 1459920Hom.: 0 Cov.: 31 AF XY: 0.00000551 AC XY: 4AN XY: 726434
GnomAD4 genome
ClinVar
Submissions by phenotype
not provided Pathogenic:9
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PS3, PS4, PM2, PM3 -
Curators: Marc Tischkowitz, Arleen D. Auerbach. Submitters to LOVD: Arleen D. Auerbach, LOVD-team, but with Curator vacancy, Marc Tischkowitz. -
Nonsense variant predicted to result in protein truncation in a gene for which loss-of-function is a known mechanism of disease; Reported in multiple individuals with PALB2-related cancers (Rahman 2007, Ding 2011, Hofstatter 2011, Antoniou 2014, Ellingson 2015, Ramus 2015).; Not observed at a significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 26296701, 19763819, 26596371, 27356891, 21618343, 21365267, 20927582, 28873162, 19584259, 17200671, 25225577, 18053174, 21153565, 18302019, 23935381, 19609323, 17200668, 21165770, 26315354, 19464302, 24998779, 25099575, 26681312, 26641009, 24728327, 28008555, 29387807, 28152038, 26283626, 19264984, 29785153, 31948886, 32546565, 31589614, 33403473, 33882707, 33420229) -
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The PALB2 c.3549C>A; p.Tyr1183Ter variant (rs118203998) is described in individuals and families affected with breast cancer, ovarian cancer and pancreatic cancer; and in Fanconi anemia when paired with another pathogenic variant on the opposite chromosome (Hoffstatter 2011, Reid 2007, Susswein 2016). This variant removes four amino acids thought to be critical in the protein structure, which may destabilize the protein (Oliver 2009). In support of this theory, cells derived from individuals harboring this variant and another truncation variant on the opposite chromosome do not produce PALB2 protein (Reid 2007). The variant is listed in the ClinVar database (Variation ID: 128144). The variant is also listed in the Genome Aggregation Database in 1 out of 246208 alleles. Considering available information, this variant is classified as pathogenic. Pathogenic PALB2 variants increase susceptibility to breast and pancreatic cancer (OMIM#601355). References: Hofstatter EW et al. PALB2 mutations in familial breast and pancreatic cancer. Fam Cancer. 2011 Jun;10(2):225-31. Oliver AW et al. Structural basis for recruitment of BRCA2 by PALB2. EMBO Rep. 2009 Sep;10(9):990-6. Reid S et al. Biallelic mutations in PALB2 cause Fanconi anemia subtype FA-N and predispose to childhood cancer. Nat Genet. 2007 Feb;39(2):162-4. Susswein LR et al. Pathogenic and likely pathogenic variant prevalence among the first 10,000 patients referred for next-generation cancer panel testing. Genet Med. 2016 Aug;18(8):823-32. -
The PALB2 c.3549C>A (p.Tyr1183*) variant alters the translational reading frame of the PALB2 mRNA and causes the premature termination of PALB2 protein synthesis. This variant has been reported in the published literature in individuals with breast, ovarian and pancreatic cancer (PMID: 26681312 (2015), 26315354 (2015), 26296701 (2015), 25099575 (2014), 21365267 (2011), 19264984 (2009)). Additionally, functional evidence suggests that this variant may impact protein function (PMID: 31757951 (2019)). The frequency of this variant in the general population, 0.000004 (1/251420 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is consistent with pathogenicity. Based on the available information, this variant is classified as pathogenic. -
Familial cancer of breast Pathogenic:6
This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation. -
Criteria applied: PVS1, PS1_MOD, PM2_SUP -
The c.3549C>A (p.Tyr1183Ter) variant in PALB2 is a nonsense variant that may cause a premature stop codon that is predicted to escape nonsense mediated decay, however it is a truncation of a functionally important region (removes amino acids 1183-1186) in a gene where loss-of-function is an established disease mechanism. This variant, or another variant leading to the same protein truncation, has been detected in three individuals with autosomal recessive FANCN. Of those individuals, three were compound heterozygous for the variant and a pathogenic or likely pathogenic variant and three of those were confirmed in trans by parental testing (co-occurring variants: c.2257C>T (p.Arg753Ter); c.2962C>T (p.Gln988Ter); c.3116delA (p.Asn1039Ilefs*2): PMID 17200671). The variant has been reported to segregate with breast and/or pancreatic cancer in 15 affected members from 6 families (Invitae; Ambry Genetics). This variant is non-functional in multiple different protein assays (PMID 31757951, PMID 31636395); however due to a lack of positive missense controls with known clinical impact, these protein assays do not meet the requirements for use by the HBOP VCEP. In summary, this variant meets the criteria to be classified as pathogenic for autosomal dominant hereditary breast and pancreatic cancer and autosomal recessive FANCN based on the ACMG/AMP criteria applied, as specified by the HBOP VCEP. (PVS1, PP1_Strong, PM3_Strong) -
This sequence change creates a premature translational stop signal (p.Tyr1183*) in the PALB2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 4 amino acid(s) of the PALB2 protein. This variant is present in population databases (rs118203998, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with breast cancer and Fanconi anemia (PMID: 17200671, 20927582, 21165770, 21365267, 26283626, 26296701). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 128144). Algorithms developed to predict the effect of variants on gene product structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this premature translational stop signal affects PALB2 function (PMID: 17200671, 19609323, 31757951). For these reasons, this variant has been classified as Pathogenic. -
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Hereditary cancer-predisposing syndrome Pathogenic:3
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The p.Y1183* pathogenic mutation (also known as c.3549C>A), located in coding exon 13 of the PALB2 gene, results from a C to A substitution at nucleotide position 3549. This changes the amino acid from a tyrosine to a stop codon within exon 13. This alteration occurs at the 3' terminus of PALB2 gene, is not expected to trigger nonsense-mediated mRNA decay, and only impacts the last four amino acids of the protein. However, premature stop codons are typically deleterious in nature and the impacted region is critical for protein function (Ambry internal data). The p.Y1183* mutation has been identified with a PALB2 pathogenic variant in multiple individuals with clinical features of Fanconi Anemia-N (FA-N) (Reid S et al. Nat. Genet. 2007 Feb;39:162-4). Lymphoblastoid cells from at least one of these patients was found to have no detectable PALB2 protein (Reid S et al. Nat. Genet. 2007 Feb;39:162-4). Truncations at this position have been reported in multiple familial breast cancer kindreds to date (Rahman N et al. Nat. Genet. 2007 Feb;39:165-7; Hofstatter EW et al. Fam. Cancer. 2011 Jun;10:225-31; Tischkowitz M et al. Hum. Mutat. 2012 Apr;33:674-80). This alteration was also identified in 4/10030 consecutive breast cancer patients referred for evaluation by an NGS hereditary cancer panel (Susswein LR et al. Genet. Med. 2016 Aug;18:823-32). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -
This variant changes 1 nucleotide in exon 13 of the PALB2 gene, creating a premature translation stop signal. Functional studies have shown that the PALB2 protein is not detectable in a carrier of this variant (PMID: 17200671) and is predicted to disrupt the BRCA2/RAD51 binding domain (PMID: 19609323). This variant has been reported in over ten individuals affected with breast or ovarian cancer (PMID: 20927582, 25099575, 26296701, 26315354, 26681312, 26641009). This variant (c.3549C>A) and a different nucleotide change resulting in the same protein consequence (c.3549C>G) have been observed in three individuals diagnosed with Fanconi anemia who also carried different pathogenic variants in the same gene (PMID: 17200671). This variant has been identified in 1/251420 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. -
Familial cancer of breast;C1835817:Fanconi anemia complementation group N;C3150547:Pancreatic cancer, susceptibility to, 3 Pathogenic:2
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PALB2-related disorder Pathogenic:1
The PALB2 c.3549C>A variant is predicted to result in premature protein termination (p.Tyr1183*). This variant has been reported in multiple individuals with breast, ovarian, or pancreatic cancer (Churpek et al. 2015. PubMed ID: 26641009; Hofstatter et al. 2011. PubMed ID: 21365267; Table S1, Susswein et al. 2015. PubMed ID: 26681312). This variant removes the last four C-terminal amino acids from the protein and is thought to contribute to protein destabilization (Oliver et al. 2009. PubMed ID: 19609323). This variant is reported in 0.00088% of alleles in individuals of European (non-Finnish) descent in gnomAD and has been interpreted by multiple laboratories as pathogenic in ClinVar, as well as the ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel (https://www.ncbi.nlm.nih.gov/clinvar/variation/128144/). Nonsense variants in PALB2 are expected to be pathogenic. This variant is interpreted as pathogenic. -
Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:1
Criteria applied: PVS1,PS1,PS4 -
Hereditary breast ovarian cancer syndrome Pathogenic:1
Variant summary: PALB2 c.3549C>A (p.Tyr1183X) 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 3.9e-06 in 258634 control chromosomes. c.3549C>A has been well reported in the literature in multiple individuals affected with several cancer phenotypes such as, epithelial ovarian cancer (Ramus_2015), in bi allelic PALB2 mediated Fanconi anemia (with p.R753*, Reid_2007), breast and pancreatic cancer (Hofstatter_2011), and male breast cancer (Ding_2011). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in no detectable PALB2 protein in lymphoblastoid cells of a patient with the Fanconi anemia phenotype, thereby confirming the null allele outcome for this variant (Reid_2007). Eight 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