ClinVar Miner

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

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Total submissions: 14
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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 Alterations resulting in premature truncation (e.g.reading frame shift, nonsense);Other strong data supporting pathogenic classification;Well-characterized mutation at same position
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 2019-12-30 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 RCV000129158 SCV000686050 pathogenic Hereditary cancer-predisposing syndrome 2020-01-15 criteria provided, single submitter clinical testing
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).
Integrated Genetics/Laboratory Corporation of America 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.
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.

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