ClinVar Miner

Submissions for variant NM_024675.4(PALB2):c.1194G>A (p.Val398=)

gnomAD frequency: 0.00103  dbSNP: rs61755173
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Total submissions: 28
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000114462 SCV000166638 benign Familial cancer of breast 2021-12-18 criteria provided, single submitter clinical testing
GeneDx RCV000212786 SCV000170868 benign not specified 2013-11-01 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 RCV000127307 SCV000212866 likely benign Hereditary cancer-predisposing syndrome 2014-06-16 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 RCV000114462 SCV000268040 likely benign Familial cancer of breast 2015-06-01 criteria provided, single submitter case-control
Illumina Laboratory Services,Illumina RCV000327932 SCV000396117 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 RCV000127307 SCV000396118 likely benign Hereditary cancer-predisposing syndrome 2016-06-14 criteria provided, single submitter clinical testing
Color Diagnostics, LLC DBA Color Health RCV000127307 SCV000685859 benign Hereditary cancer-predisposing syndrome 2015-04-13 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000588666 SCV000699523 benign not provided 2016-04-11 criteria provided, single submitter clinical testing Variant summary: Variant Summary: The c.1194G>A (p.Val398=) in PALB2 gene is a synonymous change that involves a non-conserved nucleotide with a prediction of being a "disease-causing" by mutation taster. 5/5 programs in Alamut predict that this variant does not affect normal splicing, however no functional studies supporting this notion were published at the time of evaluation. The variant is present in the control population dataset of ExAC at an overall allele frequency of 0.073% (88/121172 chrs tested), mainly in individuals of European descent (0.1154%; 77/66698 chrs tested). The observed frequency exceeds the maximum expected allele frequency for a pathogenic PALB2 variant (0.015%), suggesting that it is a common polymorphism. Based on the published reports, the variant of interest was found in affected individuals as well as in unaffected controls without personal or family history of cancer. Lastly, the variant has been reported as Benign by multiple reputable database/clinical laboratories. Taken together, the variant was classified as Benign.
PreventionGenetics,PreventionGenetics RCV000588666 SCV000807069 likely benign not provided 2017-01-12 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000212786 SCV000889569 benign not specified 2021-03-18 criteria provided, single submitter clinical testing
Mendelics RCV000114462 SCV001140041 likely benign Familial cancer of breast 2019-05-28 criteria provided, single submitter clinical testing
CeGaT Center for Human Genetics Tuebingen RCV000588666 SCV001247806 likely benign not provided 2021-10-01 criteria provided, single submitter clinical testing
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV001170350 SCV001332924 likely benign Breast and/or ovarian cancer 2019-04-09 criteria provided, single submitter clinical testing
Institute of Human Genetics, University of Leipzig Medical Center RCV000114462 SCV001429089 uncertain significance Familial cancer of breast 2018-03-06 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000588666 SCV001473704 likely benign not provided 2020-03-27 criteria provided, single submitter clinical testing
Genetic Services Laboratory,University of Chicago RCV000212786 SCV002070064 likely benign not specified 2020-10-26 criteria provided, single submitter clinical testing
Sema4,Sema4 RCV000127307 SCV002530593 likely benign Hereditary cancer-predisposing syndrome 2021-03-08 criteria provided, single submitter curation
True Health Diagnostics RCV000127307 SCV000886695 likely benign Hereditary cancer-predisposing syndrome 2018-11-19 no assertion criteria provided clinical testing
Leiden Open Variation Database RCV000588666 SCV001193071 likely benign not provided 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 RCV001357080 SCV001552421 benign Malignant tumor of breast no assertion criteria provided clinical testing The PALB2 p.Val398= variant was identified in 10 of 7040 proband chromosomes (frequency: 0.001) from individuals or families with breast and ovarian cancers of Spanish, Italian, German, and Australian nationalities and was present in 9 of 6464 control chromosomes (frequency: 0.001) from healthy individuals (Blanco 2012, Catucci 2014, Hellebrand 2011, Thompson 2015). The variant was also identified in dbSNP (ID: rs61755173) as “with Likely benign, other allele”, in ClinVar and Clinvitae databases as benign by Invitae, GeneDx, PALB2 database and likely benign by Ambry Genetics, Cancer Genetics Laboratory, Peter MacCallum Cancer Centre, and Illumina Clinical Services; and identified 2X in the LOVD 3.0 database. The variant was not identified in Cosmic, MutDB, Zhejiang Colon Cancer databases. The variant was identified in the 1000 Genomes Project in 4 of 5000 chromosomes (frequency: 0.0008) and in the NHLBI GO Exome Sequencing Project in 20 of 8600 European American African alleles. In addition, the variant was identified in control databases in 212 of 276616 chromosomes at a frequency of 0.0008 in the following populations: African in 9 of 24030 chromosomes (freq. 0.0004), Latino in 19 of 34416 chromosomes (freq. 0.0006), European Non-Finnish in 170 of 126264 chromosomes (freq. 0.001), Ashkenazi Jewish in 9 of 10148 chromosomes (freq. 0.0009), European Finnish in 1 of 25660 chromosomes (freq. 0.00004), and Other in 4 of 6454 chromosomes (freq. 0.0006) but was not seen in East Asian and South Asian POP populations increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Consortium Feb 27, 2017). The p.Val398= 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 this variant meets our laboratory's criteria to be classified as benign.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen RCV000588666 SCV001741104 likely benign not provided no assertion criteria provided clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) RCV000588666 SCV001797532 likely benign not provided no assertion criteria provided clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center RCV000212786 SCV001807038 benign not specified no assertion criteria provided clinical testing
Clinical Genetics Laboratory, Department of Pathology,Netherlands Cancer Institute RCV000588666 SCV001905847 likely benign not provided no assertion criteria provided clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht RCV000588666 SCV001927879 likely benign not provided no assertion criteria provided clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ RCV000588666 SCV001955958 likely benign not provided no assertion criteria provided clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center RCV000588666 SCV001964845 likely benign not provided no assertion criteria provided clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital RCV000212786 SCV002551681 likely benign not specified 2022-03-04 no assertion criteria provided clinical testing

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