ClinVar Miner

Submissions for variant NM_024675.4(PALB2):c.656A>G (p.Asp219Gly)

gnomAD frequency: 0.00013  dbSNP: rs45594034
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 RCV000129603 SCV000184389 likely benign Hereditary cancer-predisposing syndrome 2018-12-31 criteria provided, single submitter clinical testing In silico models in agreement (benign);Other strong data supporting benign classification
GeneDx RCV000589693 SCV000211550 likely benign not provided 2021-01-22 criteria provided, single submitter clinical testing In silico analysis supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 26283626, 20722467, 26564480, 19763884, 20122277, 21618343, 23448497, 23935836, 17200668, 25186627, 26976419, 25801821, 27621404, 26315354, 27153395, 28779002, 23555315, 29522266, 31422574)
Invitae RCV000114652 SCV000219121 likely benign Familial cancer of breast 2021-12-17 criteria provided, single submitter clinical testing
Cancer Genetics Laboratory,Peter MacCallum Cancer Centre RCV000114652 SCV000267990 uncertain significance Familial cancer of breast 2015-06-01 criteria provided, single submitter case-control
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000855601 SCV000699607 likely benign not specified 2021-03-01 criteria provided, single submitter clinical testing Variant summary: PALB2 c.656A>G (p.Asp219Gly) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0002 in 264172 control chromosomes, predominantly at a frequency of 0.00033 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 2 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 Non-Finnish European origin. c.656A>G has been reported in the literature in multiple affected individuals (including BRCA1/2 negative individuals) with limited information for an independent assessment (such as co-segregation) (example: Blanco_2013, Damiola_2015, Casas-Arozamena_2020). However, It was also observed in unaffected individuals (example: Ramus_2015, Dansonka-Mieszkowska_2010, Kraemer_2019). These reports therefore do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. To our knowledge, no experimental evidence evaluating an impact on protein function has been reported. Ten other ClinVar submitters (evaluation after 2014) cite the variant as likely benign (n=5) or uncertain significance (n=5). Based on the evidence outlined above, the variant was classified as likely benign.
Mendelics RCV000129603 SCV000839051 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-02 criteria provided, single submitter clinical testing
Color Diagnostics, LLC DBA Color Health RCV000129603 SCV000910622 likely benign Hereditary cancer-predisposing syndrome 2016-05-03 criteria provided, single submitter clinical testing
Mendelics RCV000114652 SCV001140051 uncertain significance Familial cancer of breast 2019-05-28 criteria provided, single submitter clinical testing
Division of Medical Genetics, University of Washington RCV000114652 SCV001424804 uncertain significance Familial cancer of breast 2019-07-17 criteria provided, single submitter clinical testing The c.656A>G variant has been reported in multiple individuals with breast cancer (Rahman 2007, Guenard 2010, Blanco 2013, Thompson 2015, Tung 2016), as well as healthy individuals and an individual with breast cancer who also has a BRCA2 pathogenic variant (Dansonka-Mieszkowska 2010, Ramus 2015, Tung 2016). The c.656A>G variant has an overall allele frequency of 0.0002 in the Broad Institute gnomAD Browser (https://gnomad.broadinstitute.org/). In silico analyses indicate that this variant does not alter protein structure/function. Thus, it is unknown at this time whether this variant increases cancer risk.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000589693 SCV002047316 uncertain significance not provided 2021-03-11 criteria provided, single submitter clinical testing
Genetic Services Laboratory,University of Chicago RCV000855601 SCV002070439 uncertain significance not specified 2021-12-17 criteria provided, single submitter clinical testing DNA sequence analysis of the PALB2 gene demonstrated a sequence change, c.656A>G, in exon 4 that results in an amino acid change, p.Asp219Gly. This sequence change has been described in the gnomAD database with a frequency of 0.03% in the non-Finnish European subpopulation (dbSNP rs45594034). The p.Asp219Gly change affects a poorly conserved amino acid residue located in a domain of the PALB2 protein that is not known to be functional. The p.Asp219Gly substitution appears to be benign using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). This sequence change has been previously described in individuals with PALB2-associated cancers as well as in individuals without a cancer history (PMID: 21618343, 23448497, 17200668, 20722467, 23935836, 26283626, 26976419, 20122277, 26315354, https://whi.color.com/variant/16-23647211-T-C FLOSSIES database). Due to contrasting evidences and the lack of functional studies, the clinical significance of the p.Asp219Gly change remains unknown at this time.
True Health Diagnostics RCV000129603 SCV000805279 likely benign Hereditary cancer-predisposing syndrome 2018-06-15 no assertion criteria provided clinical testing
Leiden Open Variation Database RCV000114652 SCV001192997 likely benign Familial cancer of breast 2019-05-13 no assertion criteria provided curation Curators: Marc Tischkowitz, Arleen D. Auerbach. Submitter to LOVD: Marc Tischkowitz.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital RCV000855601 SCV002551688 uncertain significance not specified 2022-04-27 no assertion criteria provided clinical testing

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.