ClinVar Miner

Submissions for variant NM_024675.4(PALB2):c.1240C>T (p.Arg414Ter) (rs180177100)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000254674 SCV000149973 pathogenic not provided 2018-08-21 criteria provided, single submitter clinical testing This variant is denoted PALB2 c.1240C>T at the cDNA level and p.Arg414Ter (R414X) at the protein level. The substitution creates a nonsense variant, which changes an Arginine to a premature stop codon (CGA>TGA), and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. This variant has been observed in multiple individuals with a personal and/or family history of breast and/or ovarian cancer (Casadei 2011, Hellebrand 2011, Kanchi 2014, Norquist 2016, Sahasrabudhe 2017). PALB2 Arg414Ter was also identified in a familial pancreatic cancer kindred (Slater 2010). This variant is considered pathogenic.
Invitae RCV000123331 SCV000166641 pathogenic Familial cancer of breast 2019-12-31 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Arg414*) in the PALB2 gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals affected with breast or ovarian cancer (PMID: 21285249, 21165770, 21618343, 22692731, 24136930, 24448499). ClinVar contains an entry for this variant (Variation ID: 128117). 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.
Ambry Genetics RCV000116064 SCV000186556 pathogenic Hereditary cancer-predisposing syndrome 2019-02-19 criteria provided, single submitter clinical testing Alterations resulting in premature truncation (e.g.reading frame shift, nonsense);Other strong data supporting pathogenic classification
Counsyl RCV000123331 SCV000488968 pathogenic Familial cancer of breast 2016-07-26 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000254674 SCV000601725 pathogenic not provided 2016-05-13 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000515305 SCV000611291 pathogenic Familial cancer of breast; Fanconi anemia, complementation group N; Pancreatic cancer 3; Tracheoesophageal fistula 2017-05-18 criteria provided, single submitter clinical testing
Color RCV000116064 SCV000685862 pathogenic Hereditary cancer-predisposing syndrome 2015-03-04 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000588541 SCV000699526 pathogenic Hereditary breast and ovarian cancer syndrome 2017-07-03 criteria provided, single submitter clinical testing Variant summary: The PALB2 c.1240C>T (p.Arg414X) variant results in a premature termination codon, predicted to cause a truncated or absent PALB2 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 (e.g. c.2167_2168delAT, p.Met723fsX21; c.2920_2921delAA, p.Lys974fsX5; c.3113G>A, p.Trp1038X). One in silico tool predicts a damaging outcome for this variant. This variant is absent in 122690 control chromosomes. The variant has been reported in numerous HBOC patients in the literature. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Mendelics RCV000116064 SCV000839042 pathogenic Hereditary cancer-predisposing syndrome 2018-07-02 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000254674 SCV001247805 pathogenic not provided 2019-10-01 criteria provided, single submitter clinical testing
Leiden Open Variation Database RCV000254674 SCV001193079 pathogenic not provided 2019-05-13 no assertion criteria provided curation Curators: Marc Tischkowitz, Arleen D. Auerbach. Submitters to LOVD: Alfons Meindl, Marc Tischkowitz.

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