ClinVar Miner

Submissions for variant NM_024675.4(PALB2):c.3257G>A (p.Arg1086Gln)

gnomAD frequency: 0.00013  dbSNP: rs146377793
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Total submissions: 13
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000130835 SCV000185733 likely benign Hereditary cancer-predisposing syndrome 2018-08-31 criteria provided, single submitter clinical testing In silico models in agreement (benign);Other data supporting benign classification
GeneDx RCV000590502 SCV000211532 uncertain significance not provided 2022-04-01 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 or endometrial cancer (Ring 2016, Momozawa 2018); Case control studies suggest this variant is not significantly associated with breast or prostate cancer (Haiman 2013); This variant is associated with the following publications: (PMID: 23555315, 27443514, 30287823, 24485656, 19609323, 20871615)
Invitae RCV000203792 SCV000260216 uncertain significance Familial cancer of breast 2021-12-17 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 1086 of the PALB2 protein (p.Arg1086Gln). This variant is present in population databases (rs146377793, gnomAD 0.05%). This missense change has been observed in individual(s) with endometrial cancer and breast cancer (PMID: 27443514, 30287823). ClinVar contains an entry for this variant (Variation ID: 142035). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The glutamine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000855603 SCV000699587 likely benign not specified 2019-02-27 criteria provided, single submitter clinical testing Variant summary: PALB2 c.3257G>A (p.Arg1086Gln) results in a conservative amino acid change located in the WD40 domain (IPR031920) of 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 6.2e-05 in 324674 control chromosomes (gnomAD and publication data), predominantly within the African subpopulation at a frequency of 0.0005 in the gnomAD database. The observed variant frequency within African control individuals in the gnomAD database is approximately 3 fold of the estimated maximal expected allele frequency for a pathogenic variant in PALB2 causing Hereditary Breast and Ovarian Cancer phenotype (0.00016). The variant was also reported in 4/2559 African American women (i.e. with an allele frequency of 0.0008), who were older than 70 years and have never had cancer (in the FLOSSIES database). These data suggest that the variant is likely a benign polymorphism found primarily in populations of African origin. c.3257G>A has been reported in the literature in individuals affected with breast cancer or endometrial carcinoma, however the variant was indicated to not be significantly associated with an increased cancer risk (Haiman 2013, Momozawa 2018). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign.
Counsyl RCV000203792 SCV000784893 uncertain significance Familial cancer of breast 2017-01-30 criteria provided, single submitter clinical testing
Mendelics RCV000130835 SCV000838998 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-02 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000590502 SCV000888373 uncertain significance not provided 2018-02-15 criteria provided, single submitter clinical testing
Color Diagnostics, LLC DBA Color Health RCV000130835 SCV000910909 likely benign Hereditary cancer-predisposing syndrome 2016-05-19 criteria provided, single submitter clinical testing
Mendelics RCV000203792 SCV001139984 uncertain significance Familial cancer of breast 2019-05-28 criteria provided, single submitter clinical testing
Genetic Services Laboratory,University of Chicago RCV000855603 SCV002070738 uncertain significance not specified 2019-10-08 criteria provided, single submitter clinical testing
National Health Laboratory Service, Universitas Academic Hospital and University of the Free State RCV002225436 SCV002504916 likely benign Hereditary breast ovarian cancer syndrome 2022-04-19 criteria provided, single submitter clinical testing
Sema4,Sema4 RCV000130835 SCV002531156 uncertain significance Hereditary cancer-predisposing syndrome 2021-08-23 criteria provided, single submitter curation
Leiden Open Variation Database RCV000855603 SCV001193380 benign not specified 2018-10-10 no assertion criteria provided curation Curators: Marc Tischkowitz, Arleen D. Auerbach. Submitter to LOVD: Yukihide Momozawa.

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