ClinVar Miner

Submissions for variant NM_024675.4(PALB2):c.1379A>G (p.Gln460Arg)

gnomAD frequency: 0.00002  dbSNP: rs749494645
Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 14
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000166836 SCV000217650 uncertain significance Hereditary cancer-predisposing syndrome 2019-02-08 criteria provided, single submitter clinical testing The p.Q460R variant (also known as c.1379A>G), located in coding exon 4 of the PALB2 gene, results from an A to G substitution at nucleotide position 1379. The glutamine at codon 460 is replaced by arginine, an amino acid with highly similar properties. This alteration has been identified in several Japanese individuals with HBOC (Nakagomi H et al. Int. J. Clin. Oncol. 2016 Apr;21:270-5; Sato K et al. Cancer Sci. 2017 Nov;108:2287-2294). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae RCV000989572 SCV000259919 likely benign Familial cancer of breast 2021-12-17 criteria provided, single submitter clinical testing
Illumina Laboratory Services,Illumina RCV000166836 SCV000396115 uncertain significance Hereditary cancer-predisposing syndrome 2016-06-14 criteria provided, single submitter clinical testing
Illumina Laboratory Services,Illumina RCV000289282 SCV000396116 uncertain significance Fanconi anemia complementation group N 2018-01-13 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
GeneDx RCV000483813 SCV000565348 uncertain significance not provided 2022-03-21 criteria provided, single submitter clinical testing In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with breast, ovarian, gastric, or prostate cancer (Nakagomi 2016, Decker 2017, Chan 2018, Momozawa 2018, Suzuki 2020, Hata 2021, Hagio 2021); This variant is associated with the following publications: (PMID: 26411315, 27701467, 28796317, 28779002, 29338689, 32566746, 33414401, 34755017, 30093976, 32426482, 30287823, 34736091)
PreventionGenetics,PreventionGenetics RCV000483813 SCV000807073 uncertain significance not provided 2017-08-02 criteria provided, single submitter clinical testing
Mendelics RCV000166836 SCV000839039 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-02 criteria provided, single submitter clinical testing
Color Diagnostics, LLC DBA Color Health RCV000166836 SCV000910808 likely benign Hereditary cancer-predisposing syndrome 2016-07-14 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000780567 SCV000917953 benign not specified 2021-10-05 criteria provided, single submitter clinical testing Variant summary: PALB2 c.1379A>G (p.Gln460Arg) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 6.8e-05 in 250890 control chromosomes, predominantly at a frequency of 0.00092 within the East Asian subpopulation in the gnomAD database. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 6 fold of the estimated maximal expected allele frequency for a pathogenic variant in PALB2 causing Hereditary Breast And Ovarian Cancer Syndrome phenotype (0.00016), strongly suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. c.1379A>G has been reported in the literature predominantly in individuals of East Asian ancestry affected with breast and/or ovarian cancer without strong evidence for causality (example, Nakagomi_2016, Sato_2017, and Chan_2018). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. At-least one co-occurrence with another pathogenic variant has been observed at our laboratory (CDH1 c.1565+2dupT), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Multiple clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Seven laboratories have classified the variant as variant of uncertain significance, three laboratories have classified the variant as likely benign and one laboratory have classified the variant Benign. Based on the evidence outlined above, the variant was classified as Benign.
Mendelics RCV000989572 SCV001140038 uncertain significance Familial cancer of breast 2019-05-28 criteria provided, single submitter clinical testing
Cancer Genomics Group,Japanese Foundation For Cancer Research RCV001030716 SCV001193684 uncertain significance Hereditary breast ovarian cancer syndrome 2019-05-01 criteria provided, single submitter research
Genetic Services Laboratory,University of Chicago RCV000780567 SCV002067197 uncertain significance not specified 2018-07-12 criteria provided, single submitter clinical testing
Sema4,Sema4 RCV000166836 SCV002530609 likely benign Hereditary cancer-predisposing syndrome 2021-07-16 criteria provided, single submitter curation
Leiden Open Variation Database RCV000780567 SCV001193094 benign not specified 2018-10-10 no assertion criteria provided curation Curators: Marc Tischkowitz, Arleen D. Auerbach. Submitter to LOVD: Yukihide Momozawa.

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.