ClinVar Miner

Submissions for variant NM_024675.3(PALB2):c.3054G>C (p.Glu1018Asp) (rs183489969)

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Total submissions: 12
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000130354 SCV000185205 likely benign Hereditary cancer-predisposing syndrome 2019-06-27 criteria provided, single submitter clinical testing No disease association in appropriately sized case-control study(ies);Subpopulation frequency in support of benign classification
GeneDx RCV000212821 SCV000211527 likely benign not specified 2017-12-20 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 RCV000114588 SCV000253601 benign Familial cancer of breast 2019-12-31 criteria provided, single submitter clinical testing
Cancer Genetics Laboratory,Peter MacCallum Cancer Centre RCV000114588 SCV000268021 uncertain significance Familial cancer of breast 2015-06-01 criteria provided, single submitter case-control
Illumina Clinical Services Laboratory,Illumina RCV000286032 SCV000396076 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 Clinical Services Laboratory,Illumina RCV000130354 SCV000396077 likely benign Hereditary cancer-predisposing syndrome 2016-06-14 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000212821 SCV000699582 benign not specified 2019-03-28 criteria provided, single submitter clinical testing Variant summary: PALB2 c.3054G>C (p.Glu1018Asp) results in a conservative amino acid change located in the Partner and localiser of BRCA2, WD40 domain (IPR031920) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00037 in 281404 control chromosomes, predominantly at a frequency of 0.0052 within the East Asian subpopulation in the gnomAD database. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 33 fold of the estimated maximal expected allele frequency for a pathogenic variant in PALB2 causing Hereditary Breast and Ovarian Cancer phenotype (0.00016), strongly suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. c.3054G>C has been reported in the literature predominantly in individuals of East Asian origin affected with Hereditary Breast and Ovarian Cancer (Casadei_2011, Tischkowitz_2012, Thompson_2015, Phuah_2013, Nguyen_Dumont_2015, Kraus_2017, Li_2015, Yang_2017). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. Co-occurrences with other pathogenic variant(s) have been reported in our internal testing database (BRCA1 c.2728delC, p.Gln910fsX90), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Four of these classified the variant as Benign/Likely benign and three classified it as a VUS. Based on the evidence outlined above, the variant was classified as benign.
GeneKor MSA RCV000130354 SCV000822112 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-01 criteria provided, single submitter clinical testing
Color RCV000130354 SCV000902643 benign Hereditary cancer-predisposing syndrome 2016-04-19 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000858970 SCV001134550 likely benign not provided 2019-04-10 criteria provided, single submitter clinical testing
Cancer Genomics Group,Japanese Foundation For Cancer Research RCV001030645 SCV001193675 uncertain significance Hereditary breast and ovarian cancer syndrome 2019-05-01 criteria provided, single submitter research
Leiden Open Variation Database RCV000114588 SCV001193337 likely benign Familial cancer of breast 2019-05-13 no assertion criteria provided curation Curators: Marc Tischkowitz, Arleen D. Auerbach. Submitters to LOVD: Marc Tischkowitz, Yukihide Momozawa.

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