Submissions for variant NM_024675.4(PALB2):c.3202-1G>C

dbSNP: rs515726111

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000160851	SCV000211529	likely pathogenic	not provided	2024-11-27	criteria provided, single submitter	clinical testing	Canonical splice site variant predicted to result in a null allele in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Observed in individual(s) with breast cancer (PMID: 26681312); This variant is associated with the following publications: (PMID: 22241545, 30890586, 37651980, Din2024[Case Report], 26681312, 38898688)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000114605	SCV000633407	pathogenic	Familial cancer of breast	2024-12-31	criteria provided, single submitter	clinical testing	This sequence change affects an acceptor splice site in intron 11 of the PALB2 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or altered protein product. This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with breast cancer (PMID: 22241545, 26681312). ClinVar contains an entry for this variant (Variation ID: 126723). Studies have shown that disruption of this splice site results in activation of a cryptic splice site, and produces a non-functional protein and/or introduces a premature termination codon (internal data). For these reasons, this variant has been classified as Pathogenic.
Mendelics	RCV000114605	SCV001139985	likely pathogenic	Familial cancer of breast	2019-05-28	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002321588	SCV002609195	likely pathogenic	Hereditary cancer-predisposing syndrome	2024-10-28	criteria provided, single submitter	clinical testing	The c.3202-1G>C intronic variant results from a G to C substitution one nucleotide upstream from coding exon 12 of the PALB2 gene. This alteration was identified in multiple individuals diagnosed with breast cancer (Susswein LR et al. Genet Med, 2016 08;18:823-32; Tischkowitz M et al. Hum Mutat, 2012 Apr;33:674-80). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration may weaken the native splice acceptor site; however, direct evidence is insufficient at this time (Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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.
Myriad Genetics, Inc.	RCV000114605	SCV004188424	likely pathogenic	Familial cancer of breast	2023-09-14	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.
Baylor Genetics	RCV000114605	SCV004202734	pathogenic	Familial cancer of breast	2022-06-09	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV002321588	SCV004357815	likely pathogenic	Hereditary cancer-predisposing syndrome	2023-03-16	criteria provided, single submitter	clinical testing	This variant causes a G to C nucleotide substitution at the -1 position of intron 11 of the PALB2 gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in two individuals affected with breast cancer (PMID: 22241545, 26681312). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of PALB2 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Likely Pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000160851	SCV005623220	likely pathogenic	not provided	2023-12-18	criteria provided, single submitter	clinical testing	The PALB2 c.3202-1G>C variant disrupts a canonical splice-acceptor site and is predicted to interfere with normal PALB2 mRNA splicing. This variant has been reported in the published literature in an individual with breast cancer (PMID: 26681312 (2015)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Based on the available information, this variant is classified as likely pathogenic.
Leiden Open Variation Database	RCV000114605	SCV001193370	likely pathogenic	Familial cancer of breast	2019-05-13	no assertion criteria provided	curation	Curators: Marc Tischkowitz, Arleen D. Auerbach. Submitter to LOVD: Marc Tischkowitz.