Submissions for variant NM_024675.4(PALB2):c.2586+10A>G

gnomAD frequency: 0.00014  dbSNP: rs373321719

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000114537	SCV000166654	likely benign	Familial cancer of breast	2024-02-01	criteria provided, single submitter	clinical testing
GeneDx	RCV000127295	SCV000170856	benign	not specified	2014-04-28	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.
Counsyl	RCV000114537	SCV000488042	likely benign	Familial cancer of breast	2015-12-18	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000588544	SCV000601764	likely benign	not provided	2022-09-08	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000580770	SCV000685959	likely benign	Hereditary cancer-predisposing syndrome	2015-06-01	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000588544	SCV000699569	likely benign	not provided	2017-05-15	criteria provided, single submitter	clinical testing	Variant summary: The PALB2 c.2586+10A>G variant involves the alteration of a non-conserved intronic nucleotide. One in silico tool predicts a benign outcome for this variant. 5/5 splice prediction tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. This variant was found in 14/121320 control chromosomes, predominantly observed in the European (Non-Finnish) subpopulation at a frequency of 0.00021 (14/66684). This frequency is about 1.4 times the estimated maximal expected allele frequency of a pathogenic PALB2 variant (0.0001563), suggesting this is likely a benign polymorphism found primarily in the populations of European (Non-Finnish) origin. This variant has been reported in the affected individuals without strong causality. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as likely benign. Taken together, this variant is classified as likely benign.
PreventionGenetics, part of Exact Sciences	RCV000588544	SCV000807091	likely benign	not provided	2016-11-22	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001118200	SCV001276466	uncertain significance	Fanconi anemia complementation group N	2018-02-12	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.
Genetic Services Laboratory, University of Chicago	RCV000127295	SCV002065736	likely benign	not specified	2021-10-15	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000127295	SCV002760826	likely benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003149782	SCV003838084	likely benign	Breast and/or ovarian cancer	2023-04-05	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000114537	SCV004019608	benign	Familial cancer of breast	2023-03-31	criteria provided, single submitter	clinical testing	This variant is considered benign. This variant is intronic and is not expected to impact mRNA splicing. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752].
Leiden Open Variation Database	RCV000588544	SCV001193251	likely benign	not provided	2019-05-13	no assertion criteria provided	curation	Curators: Marc Tischkowitz, Arleen D. Auerbach. Submitter to LOVD: Marc Tischkowitz.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001358400	SCV001554120	likely benign	Endometrial carcinoma		no assertion criteria provided	clinical testing	The PALB2 c.2586+10A>G variant was identified in 1 of 2288 proband chromosomes (frequency: 0.0004) from individuals or families with breast cancer (Casadei 2011). The variant was also identified in dbSNP (ID: rs373321719) as "With other allele", ClinVar (classified as benign by GeneDx; as likely benign by Invitae, Counsyl and four other submitters; as uncertain significance by PALB2 database), and in LOVD 3.0 (2x). The variant was identified in control databases in 29 of 276830 chromosomes at a frequency of 0.0001 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Latino in 2 of 34420 chromosomes (freq: 0.00006), European in 27 of 126668 chromosomes (freq: 0.0002); it was not observed in the African, Other, Ashkenazi Jewish, East Asian, Finnish, and South Asian populations. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.