ClinVar Miner

Submissions for variant NM_024675.4(PALB2):c.755_756CT[1] (p.Leu253fs) (rs180177092)

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Total submissions: 14
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000212779 SCV000150021 pathogenic not provided 2018-10-09 criteria provided, single submitter clinical testing This deletion of two nucleotides is denoted PALB2 c.757_758delCT at the cDNA level and p.Leu253IlefsX3 (L253IfsX3) at the protein level. The normal sequence, with the bases that are deleted in brackets, is GACT[delCT]ATCA. The deletion causes a frameshift, which changes a Leucine to an Isoleucine at codon 253, and creates a premature stop codon at position 3 of the new reading frame. This variant is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. PALB2 c.757_758delCT has been observed in individuals with breast, peritoneal, or pancreatic cancer, some of whom also had a family history of breast and/or ovarian cancer (Jones 2009, Casadei 2011, Tung 2014, Caminsky 2016, Shirts 2016). Additionally, this variant has also been reported, in the compound heterozygous state, in an individual with Fanconi anemia and a family history of breast cancer (Reid 2007). We consider this variant to be pathogenic.
Ambry Genetics RCV000116112 SCV000186591 pathogenic Hereditary cancer-predisposing syndrome 2019-04-19 criteria provided, single submitter clinical testing Alterations resulting in premature truncation (e.g.reading frame shift, nonsense);Other strong data supporting pathogenic classification
Genetic Services Laboratory, University of Chicago RCV000114659 SCV000248444 pathogenic Fanconi anemia, complementation group N 2015-03-04 criteria provided, single submitter clinical testing
Invitae RCV000114658 SCV000253946 pathogenic Familial cancer of breast 2019-12-27 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Leu253Ilefs*3) in the PALB2 gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs180177092, ExAC 0.001%). This variant has been observed in individuals affected with breast cancer (PMID: 21285249, 22006311, 26845104), and an individual affected with breast cancer and/or ovarian cancer (PMID: 26898890). It was also reported to co-occur with a second pathogenic PALB2 variant in an individual affected with Fanconi anemia (PMID: 17200671). ClinVar contains an entry for this variant (Variation ID: 126768). 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 RCV000116112 SCV000266113 pathogenic Hereditary cancer-predisposing syndrome 2015-11-20 criteria provided, single submitter clinical testing
Counsyl RCV000114658 SCV000489689 pathogenic Familial cancer of breast 2016-11-09 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000212779 SCV000601796 pathogenic not provided 2017-04-17 criteria provided, single submitter clinical testing
Color RCV000116112 SCV000686073 pathogenic Hereditary cancer-predisposing syndrome 2020-01-15 criteria provided, single submitter clinical testing
GeneKor MSA RCV000116112 SCV000821762 pathogenic Hereditary cancer-predisposing syndrome 2020-01-01 criteria provided, single submitter clinical testing This mutation is a 2 nucleotide deletion in exon 4 of the PALB2 gene. This result in a frameshift and the creation of a premature stop codon three amino acid residues later. This mutation has been described in international literature (https://grenada.lumc.nl; http://rgd.mcw.edu).
Integrated Genetics/Laboratory Corporation of America RCV000114658 SCV000917956 pathogenic Familial cancer of breast 2018-08-03 criteria provided, single submitter clinical testing Variant summary: PALB2 c.757_758delCT (p.Leu253IlefsX3) 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 (eg. c.1240C>T/p.Arg414X, c.2167_2168delAT/p.Met723fsX21). The variant allele was found at a frequency of 8.2e-06 in 123596 control chromosomes. c.757_758delCT has been reported in the literature in multiple individuals affected with Hereditary Breast and Ovarian Cancer in heterozygous state and one individual with Fanconi anemia in compound heterozygous state (Walsh_2011, Casedei_2011, Tung_2015). These data indicate that the variant is very likely to be associated with disease. Seven ClinVar submissions from other clinical diagnostic laboratories (evaluation after 2014) cite the variant as "pathogenic." Based on the evidence outlined above, the variant was classified as pathogenic.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000212779 SCV001247807 pathogenic not provided 2018-06-01 criteria provided, single submitter clinical testing
German Consortium for Hereditary Breast and Ovarian Cancer Center Cologne,University Hospital Cologne RCV000785439 SCV000924011 pathogenic Ovarian Neoplasms 2018-12-01 no assertion criteria provided research
Leiden Open Variation Database RCV000212779 SCV001193013 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.
GenomeConnect, ClinGen RCV000114658 SCV001338874 not provided Familial cancer of breast no assertion provided phenotyping only Variant interpretted as Pathogenic and reported on 02-05-2020 by Lab or GTR ID Credit Valley Hospital Department of Laboratory Medicine. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.

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