Submissions for variant NM_024675.4(PALB2):c.1685-2A>G

dbSNP: rs754660432

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000519126	SCV000618466	likely pathogenic	not provided	2018-05-16	criteria provided, single submitter	clinical testing	This variant is denoted PALB2 c.1685-2A>G or IVS4-2A>G and consists of an A>G nucleotidesubstitution at the -2 position of intron 4 of the PALB2 gene. This variant destroys a canonical splice acceptor site andis predicted to cause abnormal gene splicing, leading to either an abnormal message that is subject to nonsense-mediated mRNA decay or to an abnormal protein product. This variant has been reported in at least one individual witha personal and family history of breast and/or ovarian cancer (Li 2016). Based on the currently available information,we consider PALB2 c.1685-2A>G to be a likely pathogenic variant
Ambry Genetics	RCV000568799	SCV000665096	likely pathogenic	Hereditary cancer-predisposing syndrome	2022-10-03	criteria provided, single submitter	clinical testing	The c.1685-2A>G intronic variant results from an A to G substitution two nucleotides upstream from coding exon 5 in the PALB2 gene. This alteration was reported in one familial breast cancer cohort of 660 BRCA1/2 negative women undergoing 17 gene panel testing (Li J et al. J Med Genet, 2016 Jan;53:34-42). This alteration was also reported in a patient diagnosed with triple-negative breast cancer at age 49 (Yang XR et al. Breast Cancer Res Treat, 2017 Oct;165:687-697). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Valenzuela-Palomo A et al. J Pathol, 2022 03;256:321-334, Ambry internal data). Of note, this alteration is also designated as c.1691-2A>G in the published literature. Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as likely pathogenic.
Invitae	RCV001037839	SCV001201271	likely pathogenic	Familial cancer of breast	2024-01-18	criteria provided, single submitter	clinical testing	This sequence change affects an acceptor splice site in intron 4 of the PALB2 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs754660432, gnomAD 0.001%). Disruption of this splice site has been observed in individual(s) with personal or family history of breast and/or ovarian cancer (PMID: 26534844, 28664506). This variant is also known as c.1691-2A>G. ClinVar contains an entry for this variant (Variation ID: 449968). Studies have shown that disruption of this splice site alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 34846068; Invitae). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
PreventionGenetics, part of Exact Sciences	RCV004527630	SCV004110066	likely pathogenic	PALB2-related disorder	2023-01-24	criteria provided, single submitter	clinical testing	The PALB2 c.1685-2A>G variant is predicted to disrupt the AG splice acceptor site and interfere with normal splicing. This variant (also reported as c.1691-2A>G) was reported in individuals with a history of breast and/or ovarian cancer (Family 50, Table 1, Li et al. 2016. PubMed ID: 26534844; Table 1, Yang et al. 2017. PubMed ID: 28664506). Functional studies have also confirmed this variant impacts splicing (Table 1, Valenzuela-Palomo et al. 2021. PubMed ID: 34846068) This variant is reported in 0.00095% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/16-23641792-T-C). In ClinVar, this variant is interpreted as likely pathogenic by multiple laboratories (https://www.ncbi.nlm.nih.gov/clinvar/variation/449968/). Variants that disrupt the consensus splice acceptor site in PALB2 are expected to be pathogenic. This variant is interpreted as likely pathogenic.
Myriad Genetics, Inc.	RCV001037839	SCV004188417	likely pathogenic	Familial cancer of breast	2023-09-11	criteria provided, single submitter	clinical testing	This variant is considered likely pathogenic. This variant occurs within a consensus splice junction and is predicted to result in abnormal mRNA splicing of either an out-of-frame exon or an in-frame exon necessary for protein stability and/or normal function.