ClinVar Miner

Submissions for variant NM_024675.3(PALB2):c.3549C>G (p.Tyr1183Ter) (rs118203998)

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Total submissions: 18
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000129158 SCV000183885 pathogenic Hereditary cancer-predisposing syndrome 2018-09-11 criteria provided, single submitter clinical testing The p.Y1183* pathogenic mutation (also known as c.3549C>G), located in coding exon 13 of the PALB2 gene, results from a C to G substitution at nucleotide position 3549. This changes the amino acid from a tyrosine to a stop codon within coding exon 13. This mutation has been identified in numerous individuals with familial breast cancer and/or pancreatic cancer (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; Susswein LR et al. Genet. Med. 2016 Aug;18:823-32; Pritzlaff M et al. Breast Cancer Res. Treat. 2017 Feb;161:575-586; Dudley B et al. Cancer. 2018 Apr;124:1691-1700). In one study, an individual with clinical features of Fanconi Anemia-N (FA-N) who carried p.Y1183* in conjunction with a PALB2 frameshift mutation was found to have no detectable PALB2 protein in lymphoblastoid cells (Reid S et al. Nat. Genet. 2007 Feb;39:162-4). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation. As such, this alteration is interpreted as a disease-causing mutation.
GeneDx RCV000212830 SCV000211538 pathogenic not provided 2018-12-11 criteria provided, single submitter clinical testing This pathogenic variant is denoted PALB2 c.3549C>G at the cDNA level and p.Tyr1183Ter (Y1183X) at the protein level. The substitution creates a nonsense variant, which changes a Tyrosine to a premature stop codon (TAC>TAG), and is predicted to cause loss of normal protein function through protein truncation. This variant and a different nucleotide substitution at the same position, c.3549C>A, resulting in the same nonsense variant at the protein level, have been reported in multiple individuals with a personal and/or family history of melanoma, breast, and other cancers, and was observed in the compound heterozygous state with other truncating PALB2 variants in two individuals with Fanconi Anemia (Rahman 2007, Reid 2007, Ding 2011, Antoniou 2014, Thompson 2015). We consider this variant to be pathogenic.
Invitae RCV000114634 SCV000253945 pathogenic Familial cancer of breast 2020-10-26 criteria provided, single submitter clinical testing This sequence change results in a premature translational stop signal in the PALB2 gene (p.Tyr1183*). While this is not anticipated to result in nonsense mediated decay, it is expected to delete the last 4 amino acids of the PALB2 protein. This variant is present in population databases (rs118203998, ExAC 0.003%). This variant has been observed in individuals affected with breast, ovarian and pancreatic cancer, and Fanconi anemia (PMID: 17200668, 26315354, 17200671, 21365267, 22241545). ClinVar contains an entry for this variant (Variation ID: 1245). Experimental studies have shown that this variant prevents closure of the WD40 ring structure and destabilizes the PALB2 protein in cell culture (PMID: 19609323). In addition, while truncating mutations close to the end of a protein are generally expected to escape nonsense-mediated RNA decay, there was no detectable PALB2 protein in lymphoblastoid cells from two individuals carrying this variant, indicating that the mutation results in a null allele (PMID: 17200671). Loss-of-function variants in PALB2 are known to be pathogenic (PMID: 17200668, 24136930, 25099575). For these reasons, this variant has been classified as Pathogenic.
University of Washington Department of Laboratory Medicine, University of Washington RCV000129158 SCV000266110 pathogenic Hereditary cancer-predisposing syndrome 2015-11-20 criteria provided, single submitter clinical testing
Cancer Genetics Laboratory,Peter MacCallum Cancer Centre RCV000114634 SCV000267976 likely pathogenic Familial cancer of breast 2015-06-01 criteria provided, single submitter case-control
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000212830 SCV000604598 pathogenic not provided 2017-05-09 criteria provided, single submitter clinical testing The PALB2 c.3549C>G;p.Tyr1183Ter variant has been described in individuals and families affected with breast cancer and Fanconi anemia (Rahman 2007, Reid 2007, Tischkowitz 2012). 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 with this variant do not produce PALB2 protein (Reid 2007). The variant is listed in the ClinVar database (Variation ID: 1245) and the dbSNP variant database (rs118203998) with an allele frequency of 0.001625 percent in the Genome Aggregation Database. Considering available information, this variant is classified as pathogenic. Pathogenic PALB2 variants increase susceptibility to breast and pancreatic cancer (OMIM#601355). References: Oliver AW et al. Structural basis for recruitment of BRCA2 by PALB2. EMBO Rep. 2009 Sep;10(9):990-6. Rahman N et al. PALB2, which encodes a BRCA2-interacting protein, is a breast cancer susceptibility gene. Nat Genet. 2007 Feb;39(2):165-7. 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. Tischkowitz M et al. Rare germline mutations in PALB2 and breast cancer risk: a population-based study. Hum Mutat. 2012 Apr;33(4):674-80.
Counsyl RCV000114634 SCV000677737 pathogenic Familial cancer of breast 2015-11-13 criteria provided, single submitter clinical testing
Color Health, Inc RCV000129158 SCV000686050 pathogenic Hereditary cancer-predisposing syndrome 2020-08-20 criteria provided, single submitter clinical testing This variant changes 1 nucleotide in exon 13 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 individuals affected with breast cancer (PMID: 25099575, 25225577) and in individuals affected with Fanconi anemia in compound heterozygous state with pathogenic variants (PMID: 17200671). This variant has been identified in 4/251420 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.
GeneKor MSA RCV000212830 SCV000821759 pathogenic not provided 2020-01-01 criteria provided, single submitter clinical testing This variant is a single amino acid change from Tyrosine to a Termination codon at amino acid residue 1183 of the PALB2 gene and it is expected to delete the last 4 amino acids of the PALB2 protein. This variant has been reported in individuals affected with breast, ovarian and pancreatic cancer, and Fanconi anemia (PMID: 17200668, 26315354, 17200671, 21365267, 22241545). Experimental studies have shown that this variant prevents closure of the WD40 ring structure and destabilizes the PALB2 protein in cell culture (PMID: 19609323). Truncating variants in PALB2 are known to be pathogenic. The mutation database Clinvar contains entries for this variant (Variation ID: 1245).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000114634 SCV001362219 pathogenic Familial cancer of breast 2019-11-29 criteria provided, single submitter clinical testing Variant summary: PALB2 c.3549C>G (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. Another truncation at this position has been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 1.6e-05 in 251420 control chromosomes. c.3549C>G has been reported in the literature in multiple individuals affected with Breast Cancer as well as Fanconi Anemia (e.g. Antoniou_2014, Susswein_2016, Reid_2007). These data indicate that the variant is very likely to be associated with disease. Nine 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/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Illumina Clinical Services Laboratory,Illumina RCV001270735 SCV001451483 pathogenic PALB2-Related Disorders 2019-01-29 criteria provided, single submitter clinical testing The PALB2 c.3549C>G (p.Tyr1183Ter) variant is a stop-gained variant that is predicted to result in a truncated protein. Across a selection of the available literature, the p.Tyr1183Ter variant has been reported in a heterozygous state in five individuals with familial breast cancer, including in one bilateral and one male case (Rahman et al. 2007; Ding et al. 2011; Tischkowitz et al. 2012). The variant has also been reported in trans with a second null variant in two unrelated individuals with Fanconi anemia (Reid et al. 2007). A different nucleotide change resulting in the same amino acid change has also been reported in a compound heterozygous state in an individual with Fanconi anemia (Reid et al. 2007). The p.Tyr1183Ter variant was absent from 1260 control individuals but is reported at a frequency of 0.000035 in the European (non-Finnish) population of the Genome Aggregation Database. Structural studies based on X-ray crystallography predict that loss of the last four residues of PALB2 caused by p.Tyr1183Ter disrupts the hydrogen bonding in the seventh blade of the beta-propeller, resulting in a misfolded and quickly degraded protein (Oliver et al. 2009). This prediction is consistent with the lack of detectable protein expression found in lymphoblastoid cells from compound heterozygous patients with Fanconi anemia (Reid et al. 2007). Based on the collective evidence, the p.Tyr1183Ter variant is classified as pathogenic for PALB2-related disorders.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000212830 SCV001470046 pathogenic not provided 2019-11-21 criteria provided, single submitter clinical testing The variant creates a premature nonsense codon, and is therefore predicted to result in the loss of a functional protein. Found in at least one patient with expected phenotype for this gene, and found in general population data at a frequency that is consistent with pathogenicity.
Department of Molecular Diagnostics, Institute of Oncology Ljubljana RCV000114634 SCV001499697 likely pathogenic Familial cancer of breast 2020-04-02 criteria provided, single submitter clinical testing
OMIM RCV000001304 SCV000021454 pathogenic Fanconi anemia, complementation group N 2007-02-01 no assertion criteria provided literature only
OMIM RCV000001305 SCV000021455 risk factor Breast cancer, susceptibility to 2007-02-01 no assertion criteria provided literature only
ITMI RCV000121742 SCV000085940 not provided not specified 2013-09-19 no assertion provided reference population
Leiden Open Variation Database RCV000212830 SCV001193428 pathogenic not provided 2019-05-13 no assertion criteria provided curation Curators: Marc Tischkowitz, Arleen D. Auerbach. Submitters to LOVD: Arleen D. Auerbach, LOVD-team, but with Curator vacancy, Marc Tischkowitz.
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001355428 SCV001550311 pathogenic Pancreatic cancer 3 no assertion criteria provided clinical testing The PALB2 p.Tyr1183* variant was identified in 11 of 15,266 proband chromosomes (frequency: 0.0007) from individuals or families with Fanconi anemia or ovarian, breast or pancreatic cancer and was not identified in 13,140 control chromosomes from healthy individuals (Reid 2007, Rahman 2007, Ramus 2015, Hofstatter 2011, Tischkowitz 2012, Thompson 2015, Ding 2011). The variant was identified in dbSNP (rs118203998) as “with pathogenic allele, ClinVar (classified as pathogenic by Invitae, Color, GeneDx, Ambry Genetics and 8 other submitters; and as likely pathogenic by Peter MacCallum Cancer Centre) and LOVD 3.0 (observed 13x). The variant was identified in control databases in 4 of 246,208 chromosomes at a frequency of 0.00002 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the European population in 4 of 111,674 chromosomes (freq: 0.00004); it was not observed in the African, Other, Latino, Ashkenazi Jewish, East Asian, Finnish or South Asian populations. The c.3549C>G variant leads to a premature stop codon at position 1183; this position is 4 residues from the C-terminus of the protein, which is not usually predicted to result in non-sense mediated decay. However, the PALB2 protein was absent in lymphoblastoid cells derived from patients expressing this variant (Reid 2007). Analysis of the PALB2 protein structure likely explains this protein absence as this variant is predicted to destabilize the PALB2 protein by preventing closure of the ring structure, resulting in incomplete protein folding and rapid degradation (Oliver 2009). Loss of function variants of the PALB2 gene are an established mechanism of disease in hereditary breast and ovarian 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.

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