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

gnomAD frequency: 0.00021  dbSNP: rs45594034

Total submissions: 14

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	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
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	2024-02-01	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	2022-09-22	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. Thirteen other ClinVar submitters (evaluation after 2014) cite the variant as likely benign (n=6) or uncertain significance (n=7). Based on the evidence outlined above, the variant was classified as likely benign.
Color Diagnostics, LLC DBA Color Health	RCV000129603	SCV000910622	likely benign	Hereditary cancer-predisposing syndrome	2016-05-03	criteria provided, single submitter	clinical testing
Mendelics	RCV003492444	SCV001140051	likely benign	Hereditary cancer	2024-01-23	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	2022-12-27	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.0003253 (42/129110 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in individuals affected with breast cancer (PMIDs: 33471991 (2021); see also LOVD3 Shared (https://databases.lovd.nl/shared/), 26976419 (2016), 26283626 (2015), 23935836 (2013), 23448497 (2013), and 19763884 (2010)). In addition, it has been reported in healthy cancer-free individuals (FLOSSIES (https://whi.color.com/), PMIDs: 33471991 (2021); see also LOVD3 Shared (https://databases.lovd.nl/shared/), 26315354 (2015), and 20122277 (2010)). It has also been reported in an individual with head and neck squamous cell carcinoma (PMID: 28678401 (2017)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant.
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.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000855601	SCV002551688	uncertain significance	not specified	2024-02-06	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004542814	SCV004774309	uncertain significance	PALB2-related disorder	2023-11-16	criteria provided, single submitter	clinical testing	The PALB2 c.656A>G variant is predicted to result in the amino acid substitution p.Asp219Gly. This variant has been reported in multiple individuals with a personal and/or family history of pancreatic and breast cancers (Tung et al. 2015. PubMed ID: 25186627; Tung et al. 2016. PubMed ID: 26976419; Blanco et al. 2013. PubMed ID: 23935836; Thompson et al. 2015. PubMed ID: 26283626; Supplementary Table 1, Rahman et al. 2007. PubMed ID: 17200668). It has been reported in a non-cancer cohort and also healthy control individuals (Table 4, Dansonka-Mieszkowska et al. 2010. PubMed ID: 20122277; Table S4, Ramus et al. 2015. PubMed ID: 26315354; Kraemer et al. 2019. PubMed ID: 31422574). It has also been reported in an individual with breast cancer that harbored a pathogenic truncating BRCA2 variant (Table A1 and A2, Study ID BOB20988WB, Tung et al. 2016. PubMed ID: 26976419). This variant is reported in 0.033% of alleles in individuals of European (Non-Finnish) descent in gnomAD and has conflicting interpretations of likely benign and uncertain significance in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/126763/). Although we suspect that this variant is likely benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
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.