ClinVar Miner

Submissions for variant NM_024675.3(PALB2):c.2509G>A (p.Glu837Lys) (rs587778587)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 12
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000656936 SCV000149996 uncertain significance not provided 2018-01-09 criteria provided, single submitter clinical testing This variant is denoted PALB2 c.2509G>A at the cDNA level, p.Glu837Lys (E837K) at the protein level, and results in the change of a Glutamic Acid to a Lysine (GAA>AAA). This variant has been reported in several individuals, all of whom are of Asian ancestry, with personal and/or family history of breast/ovarian cancer (Nakagomi 2015, Kim 2017, Sato 2017). PALB2 Glu837Lys was also identified in 1/62 healthy East Asian individuals undergoing whole genome sequencing (Bodian 2014). Of note, the participants in this study were younger than 50 years old thus the unaffected status of this individual may not be significant. PALB2 Glu837Lys was observed at an allele frequency of 0.13% (24/18,870) in individuals of East Asian ancestry in large population cohorts (Lek 2016). This variant is located in a region that interacts with BRCA2 and is required for interaction with POLH and POLH DNA synthesis stimulation (Oliver 2009, Buisson 2014). In-silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether PALB2 Glu837Lys is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000116087 SCV000172832 uncertain significance Hereditary cancer-predisposing syndrome 2018-06-29 criteria provided, single submitter clinical testing Insufficient evidence;In silico models in agreement (benign)
Invitae RCV000989556 SCV000290839 likely benign Familial cancer of breast 2019-12-31 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000318539 SCV000396094 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.
Illumina Clinical Services Laboratory,Illumina RCV000116087 SCV000396095 likely benign Hereditary cancer-predisposing syndrome 2016-06-14 criteria provided, single submitter clinical testing
Color RCV000116087 SCV000902868 likely benign Hereditary cancer-predisposing syndrome 2016-04-05 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000121758 SCV000917952 likely benign not specified 2018-03-23 criteria provided, single submitter clinical testing Variant summary: PALB2 c.2509G>A (p.Glu837Lys) 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 0.00014 in 122060 control chromosomes, predominantly found within the East Asian subpopulation at a frequency of 0.0017 in the ExAC database. The observed variant frequency within East Asian control individuals in the ExAC database is approximately 11 fold of the estimated maximal expected allele frequency for a pathogenic variant in PALB2 causing Hereditary Breast and Ovarian Cancer phenotype (0.0017 vs. 0.00016), strongly suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. Though c.2509G>A has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer (Nakagomi 2015, Kim 2017, Sato 2017) and in a patient with Beckwith-Wiedemann syndrome and hepatoblastoma (Kim 2017), these patients were all of East Asian origin. One of these studies also noted that the frequency of the variant among the patients was not significantly different from those observed among apparently healthy Japanese individuals registered in the HGVD database (Sato 2017). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Two laboratories classified this variant as likely benign and two classified as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign.
Mendelics RCV000989556 SCV001140004 likely benign Familial cancer of breast 2019-05-28 criteria provided, single submitter clinical testing
Cancer Genomics Group,Japanese Foundation For Cancer Research RCV001030647 SCV001193677 uncertain significance Hereditary breast and ovarian cancer syndrome 2019-05-01 criteria provided, single submitter research
ITMI RCV000121758 SCV000085956 not provided not specified 2013-09-19 no assertion provided reference population
True Health Diagnostics RCV000116087 SCV000805277 uncertain significance Hereditary cancer-predisposing syndrome 2018-05-01 no assertion criteria provided clinical testing
Leiden Open Variation Database RCV000121758 SCV001193239 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.