Submissions for variant NM_024675.4(PALB2):c.2996+9del

dbSNP: rs769414858

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000197031	SCV000253599	benign	Familial cancer of breast	2024-01-31	criteria provided, single submitter	clinical testing
Counsyl	RCV000197031	SCV000488363	uncertain significance	Familial cancer of breast	2016-03-08	criteria provided, single submitter	clinical testing
GeneDx	RCV000478607	SCV000565355	benign	not specified	2015-04-30	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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV003477663	SCV000601774	likely benign	not provided	2023-06-30	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000580718	SCV000685999	likely benign	Hereditary cancer-predisposing syndrome	2016-06-22	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000478607	SCV000699581	benign	not specified	2019-04-04	criteria provided, single submitter	clinical testing	Variant summary: PALB2 c.2996+9delA alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 5.4e-05 in 277172 control chromosomes, predominantly at a frequency of 0.00058 within the African subpopulation in the gnomAD database. The observed variant frequency within African control individuals in the gnomAD database is approximately 3.7 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 African origin. To our knowledge, no occurrence of c.2996+9delA in individuals affected with Hereditary Breast and Ovarian Cancer and no experimental evidence demonstrating its impact on protein function have been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Four classified the variant as Benign/Likely benign while one classified the variant as Uncertain significance. Based on the evidence outlined above, the variant was classified as benign.
Mendelics	RCV000197031	SCV001139991	likely benign	Familial cancer of breast	2019-05-28	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000580718	SCV002530744	likely benign	Hereditary cancer-predisposing syndrome	2020-12-15	criteria provided, single submitter	curation
Myriad Genetics, Inc.	RCV000197031	SCV004019137	benign	Familial cancer of breast	2023-03-30	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].
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001354543	SCV001549187	likely benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The PALB2 c.2996+9del variant was not identified in the literature nor was it identified in the LOVD 3.0 database. The variant was identified in dbSNP (ID: rs769414858) as "With other allele" and in ClinVar (classified as benign by Invitae and GeneDx; as likely benign by two submitters; and as uncertain significance by Myriad Women's Health and one other submitter). The variant was not identified in the Genome Aggregation Database (Feb 27, 2017). 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.