ClinVar Miner

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

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 15
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
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.
Ambry Genetics RCV000129158 SCV000183885 pathogenic Hereditary cancer-predisposing syndrome 2017-08-22 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Alterations resulting in premature truncation (e.g.reading frame shift, nonsense),Other strong data supporting pathogenic classification,Well-characterized mutation at same position
Cancer Genetics Laboratory,Peter MacCallum Cancer Centre RCV000114634 SCV000267976 likely pathogenic Familial cancer of breast 2015-06-01 criteria provided, single submitter case-control
Color RCV000129158 SCV000686050 pathogenic Hereditary cancer-predisposing syndrome 2016-05-02 criteria provided, single submitter clinical testing
Counsyl RCV000114634 SCV000677737 pathogenic Familial cancer of breast 2015-11-13 criteria provided, single submitter clinical testing
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.
GeneKor MSA RCV000212830 SCV000821759 pathogenic not provided 2018-08-01 criteria provided, single submitter clinical testing
ITMI RCV000121742 SCV000085940 not provided not specified 2013-09-19 no assertion provided reference population
Invitae RCV000114634 SCV000253945 pathogenic Familial cancer of breast 2018-06-29 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 reported 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.
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
PALB2 database RCV000114634 SCV000148580 pathogenic Familial cancer of breast 2012-10-18 no assertion criteria provided literature only
PALB2 database RCV000001304 SCV000148581 pathogenic Fanconi anemia, complementation group N 2012-10-18 no assertion criteria provided literature only
PALB2 database RCV000114635 SCV000148582 pathogenic Pancreatic cancer 3 2012-10-18 no assertion criteria provided literature only
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

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.