ClinVar Miner

Submissions for variant NM_024675.4(PALB2):c.1470C>T (p.Pro490=)

gnomAD frequency: 0.00035  dbSNP: rs45612837
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Total submissions: 22
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000114476 SCV000166643 benign Familial cancer of breast 2021-12-17 criteria provided, single submitter clinical testing
GeneDx RCV000212795 SCV000170871 benign not specified 2014-02-28 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Ambry Genetics RCV000127310 SCV000212958 likely benign Hereditary cancer-predisposing syndrome 2014-08-01 criteria provided, single submitter clinical testing This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Cancer Genetics Laboratory,Peter MacCallum Cancer Centre RCV000114476 SCV000268043 likely benign Familial cancer of breast 2015-06-01 criteria provided, single submitter case-control
Illumina Laboratory Services,Illumina RCV000276625 SCV000396113 likely benign Fanconi anemia complementation group N 2017-04-27 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Illumina Laboratory Services,Illumina RCV000127310 SCV000396114 likely benign Hereditary cancer-predisposing syndrome 2016-06-14 criteria provided, single submitter clinical testing
Color Diagnostics, LLC DBA Color Health RCV000127310 SCV000685883 likely benign Hereditary cancer-predisposing syndrome 2015-04-02 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000586468 SCV000699536 benign not provided 2016-12-22 criteria provided, single submitter clinical testing Variant summary: The PALB2 c.1470C>T (p.Pro490Pro) variant involves the alteration of a non-conserved nucleotide, resulting in a synonymous change. One in silico tool predicts a benign outcome for this variant. 5/5 splice prediction tools predict no significant impact on normal splicing. ESE finder predicts that this variant may affect ESE sites. However, these predictions have yet to be confirmed by functional studies. This variant was found in 40/128736 control chromosomes, predominantly observed in the European (Non-Finnish) subpopulation at a frequency of 0.0004196 (28/66726). This frequency is about 3 times the estimated maximal expected allele frequency of a pathogenic PALB2 variant (0.0001563), suggesting this is likely a benign polymorphism found primarily in the populations of European (Non-Finnish) origin. This variant has been reported in multiple affected individuals without strong evidence for causality. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as benign/likely benign. Taken together, this variant is classified as benign.
Counsyl RCV000114476 SCV000786234 likely benign Familial cancer of breast 2018-04-03 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000212795 SCV000889572 benign not specified 2020-01-03 criteria provided, single submitter clinical testing
Mendelics RCV000114476 SCV001140035 likely benign Familial cancer of breast 2019-05-28 criteria provided, single submitter clinical testing
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV001798293 SCV002043584 likely benign Breast and/or ovarian cancer 2020-07-03 criteria provided, single submitter clinical testing
Genetic Services Laboratory,University of Chicago RCV000212795 SCV002066590 likely benign not specified 2019-09-24 criteria provided, single submitter clinical testing
Sema4,Sema4 RCV000127310 SCV002530616 likely benign Hereditary cancer-predisposing syndrome 2020-11-19 criteria provided, single submitter curation
CeGaT Center for Human Genetics Tuebingen RCV000586468 SCV002545768 likely benign not provided 2022-04-01 criteria provided, single submitter clinical testing
True Health Diagnostics RCV000127310 SCV000788084 likely benign Hereditary cancer-predisposing syndrome 2017-08-14 no assertion criteria provided clinical testing
Leiden Open Variation Database RCV000114476 SCV001193111 benign Familial cancer of breast 2019-05-13 no assertion criteria provided curation Curators: Marc Tischkowitz, Arleen D. Auerbach. Submitter to LOVD: Marc Tischkowitz.
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000586468 SCV001554228 likely benign not provided no assertion criteria provided clinical testing The PALB2 p.Pro490= variant was identified in 5 of 4506 proband chromosomes (frequency: 0.001) from individuals or families with breast and/or ovarian cancer and 3 of 2168 control chromosomes (frequency 0.001; Hartley 2014, Adank 2011, Nguyen-Dumont 2013, Teo 2013, Bogdanova 2011, Rahman 2007). The variant was also identified in ClinVar (2x benign: Invitae, GeneDx; 5x Likely Benign: Ambry Genetics, MacCallum Cancer Genetics, Illumina, PALB2 database), LOVD 3.0 (4x as "probably does not affect function"), and the Zhejiang University Database (2x as "probably no pathogenicity"). The variant was not identified in the COSMIC or MutDB databases. The variant was identified in control databases in 75 of 277162 chromosomes at a frequency of 0.0003, increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Consortium Feb 27, 2017). The p.Pro490= variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. In addition, in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) RCV000586468 SCV001797721 likely benign not provided no assertion criteria provided clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center RCV000586468 SCV001807651 likely benign not provided no assertion criteria provided clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht RCV000586468 SCV001931937 likely benign not provided no assertion criteria provided clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ RCV000586468 SCV001959339 likely benign not provided no assertion criteria provided clinical testing

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