ClinVar Miner

Submissions for variant NM_024675.4(PALB2):c.2258G>A (p.Arg753Gln)

gnomAD frequency: 0.00003  dbSNP: rs587778586
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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000121757 SCV000211514 likely benign not specified 2018-01-17 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.
Invitae RCV000195647 SCV000255084 likely benign Familial cancer of breast 2021-11-17 criteria provided, single submitter clinical testing
Genetic Services Laboratory,University of Chicago RCV000121757 SCV000596212 uncertain significance not specified 2017-03-13 criteria provided, single submitter clinical testing
Ambry Genetics RCV000561765 SCV000666872 likely benign Hereditary cancer-predisposing syndrome 2018-07-16 criteria provided, single submitter clinical testing In silico models in agreement (benign);Other strong data supporting benign classification
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000121757 SCV000699557 likely benign not specified 2022-02-24 criteria provided, single submitter clinical testing Variant summary: PALB2 c.2258G>A (p.Arg753Gln) 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 2.1e-05 in 282886 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. The variant, c.2258G>A, has been reported in the literature in an individual affected with breast cancer (Dorling_2021), but it was also found in several healthy controls (Bodian_2014, Momozawa_2018, Dorling_2021). In addition, a co-occurrence with another pathogenic variant has been reported (BRCA2 c.5130_5133delTGTA (p.Tyr1710X); in an internal LCA sample), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eight other submitters have provided clinical-significance assessments for this variant in ClinVar after 2014 without evidence for independent evaluation, and classified the variant as VUS (n=4) or likely benign (n=4). Based on the evidence outlined above, the variant was classified as likely benign.
Counsyl RCV000195647 SCV000786195 uncertain significance Familial cancer of breast 2018-03-14 criteria provided, single submitter clinical testing
Mendelics RCV000561765 SCV000839022 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-02 criteria provided, single submitter clinical testing
Color Diagnostics, LLC DBA Color Health RCV000561765 SCV000903011 likely benign Hereditary cancer-predisposing syndrome 2015-11-02 criteria provided, single submitter clinical testing
Sema4,Sema4 RCV000561765 SCV002530679 likely benign Hereditary cancer-predisposing syndrome 2021-04-30 criteria provided, single submitter curation
ITMI RCV000121757 SCV000085955 not provided not specified 2013-09-19 no assertion provided reference population
Leiden Open Variation Database RCV000588075 SCV001193203 uncertain significance not provided 2018-10-10 no assertion criteria provided curation Curators: Marc Tischkowitz, Arleen D. Auerbach. Submitter to LOVD: Yukihide Momozawa.

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