Submissions for variant NM_024675.4(PALB2):c.3350+5G>A

gnomAD frequency: 0.00001  dbSNP: rs587782566

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000131789	SCV000186838	likely pathogenic	Hereditary cancer-predisposing syndrome	2025-03-05	criteria provided, single submitter	clinical testing	The c.3350+5G>A intronic variant results from a G to A substitution 5 nucleotides after coding exon 12 in the PALB2 gene. This nucleotide position is highly conserved in available vertebrate species. This alteration has been identified in the homozygous state in an individual with Fanconi Anemia features, and RNA analysis showed skipping of coding exon 12 (Mori M et al. Haematologica. 2019 Oct;104:1962-1973). This variant has also been reported in a Chinese patient with pancreatic ductal adenocarcinoma (Jiang H et al. Mol Genet Genomic Med, 2023 Jul;11:e2170). In silico splice site analysis for this alteration is inconclusive. RNA studies have demonstrated this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000526519	SCV000633424	pathogenic	Familial cancer of breast	2024-12-16	criteria provided, single submitter	clinical testing	This sequence change falls in intron 12 of the PALB2 gene. It does not directly change the encoded amino acid sequence of the PALB2 protein. RNA analysis indicates that this variant induces altered splicing and likely disrupts the C-terminus of the protein. This variant is present in population databases (rs587782566, gnomAD 0.006%). This variant has been observed in individual(s) with Fanconi anemia (PMID: 30792206). ClinVar contains an entry for this variant (Variation ID: 142586). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in the generation of two aberrant transcripts, one that leads to out-of-frame exon 12 skipping and the other that leads to the in-frame skipping of exons 11 and 12 together and introduces a new termination codon (PMID: 30890586, 32133419; internal data). However the mRNA is not expected to undergo nonsense-mediated decay. This variant disrupts a region of the PALB2 protein in which other variant(s) (p.Tyr1183*) have been determined to be pathogenic (PMID: 17200671, 20927582, 21165770, 21365267, 26283626, 26296701). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Mendelics	RCV000131789	SCV000838994	likely pathogenic	Hereditary cancer-predisposing syndrome	2023-03-30	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000131789	SCV001358405	likely pathogenic	Hereditary cancer-predisposing syndrome	2023-02-21	criteria provided, single submitter	clinical testing	This variant causes a G to A nucleotide substitution at the +5 position of the intron 12 splice donor site of the PALB2 gene. Four RNA studies have reported aberrant mRNA transcripts in variant carriers and in one minigene splicing assay that are predicted to disrupt the BRCA2 and RAD51 binding domain in the protein (PMID: 30792206, 30890586, 32133419, 32238468, 34846068). One of the aberrant transcript is also present in healthy controls, albeit at a lower average level than in carriers with this variant (PMID: 32133419). This variant has been reported in two individuals affected with breast cancer, one individual affected with pancreatic cancer who also has a ATM truncation variant, and another individual affected with ovarian cancer (PMID: 29731985, 34793666, 35676859). The variant also has been observed in a homozygous carrier affected with Fanconi anemia (PMID: 30792206, 32238468). This variant has been identified in 2/251408 chromosomes 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001824643	SCV002074502	likely pathogenic	Hereditary breast ovarian cancer syndrome	2022-01-31	criteria provided, single submitter	clinical testing	Variant summary: PALB2 c.3350+5G>A alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. One computational tool predicts the variant weakens a 5' donor site. Experimental evidence from multiple studies demonstrate that this variant affects mRNA splicing leading to aberrant transcripts, most significantly to skipping of exon 12 (Karam_2019, Lopez-Perolio_2019, Mori_2019, Landrith_2020). Some of these studies identified naturally occurring alternative splicing event(s) leading to skipping of exon 12. However, the variant causes a significant increase to the level of alternative splicing resulting in skipping of this exon. The predicted protein encoded by this transcript is unlikely to be functional, as it lacks part of the C-terminal WD40 beta-propeller domain that mediates PALB2 interaction with several key homologous recombination proteins, including BRCA2 and RAD51 (Lopez-Perolio_2019, Landrith_2020). The variant allele was found at a frequency of 8e-06 in 251408 control chromosomes (gnomAD). c.3350+5G>A has been reported in the literature in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome and pancreatic ductal adenocarcinoma (e.g. Kondo_2018, Landrith_2020). It was also reported in a homozygous individual affected with Fanconi Anemia (Mori_2019). Three ClinVar submitters (evaluation after 2014) cite the variant as likely pathogenic and one ClinVar submitter (evaluation after 2014) cites it as uncertain significance. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Sema4, Sema4	RCV000131789	SCV002531173	likely pathogenic	Hereditary cancer-predisposing syndrome	2021-01-27	criteria provided, single submitter	curation
Myriad Genetics, Inc.	RCV000526519	SCV004043220	likely pathogenic	Familial cancer of breast	2023-10-06	criteria provided, single submitter	clinical testing	This variant is considered likely pathogenic. mRNA analysis has demonstrated abnormal mRNA splicing occurs [PMID: 30792206, 32133419, 34846068]. This variant has been observed homozygous in one or more individuals with Fanconi Anemia [PMID: 30792206].
Baylor Genetics	RCV000526519	SCV004202110	likely pathogenic	Familial cancer of breast	2023-08-28	criteria provided, single submitter	clinical testing
Juno Genomics, Hangzhou Juno Genomics, Inc	RCV004796031	SCV005417798	likely pathogenic	Fanconi anemia complementation group N; Pancreatic cancer, susceptibility to, 3; Breast-ovarian cancer, familial, susceptibility to, 5		criteria provided, single submitter	clinical testing	PVS1+PM3_Supporting
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV004998280	SCV005623228	likely pathogenic	not provided	2024-10-15	criteria provided, single submitter	clinical testing	The PALB2 c.3350+5G>A variant has been reported in the published literature in individuals affected with pancreatic cancer (PMID: 29731985 (2019), 36978154 (2023)), breast cancer (PMID: 34793666 (2022), 36003761 (2022), 38355628 (2024)), and ovarian cancer (PMID: 35676859 (2022)). This variant has also been reported in a homozygous state in an individual with Fanconi anemia (PMID: 30792206 (2019)). Assessment of experimental evidence suggests this variant results in abnormal RNA splicing, causing skipping of exon 12 (PMID: 30792206 (2019), 34846068 (2022)) or skipping of exons 11 and 12 (PMID: 30890586 (2019)). The frequency of this variant in the general population, 0.000008 (2/251408 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using software algorithms for the prediction of the effect of nucleotide changes on PALB2 mRNA splicing yielded inconclusive findings. Based on the available information, this variant is classified as likely pathogenic.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV005359282	SCV005913276	likely pathogenic	Breast-ovarian cancer, familial, susceptibility to, 5	2024-11-05	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004739459	SCV005347930	likely pathogenic	PALB2-related disorder	2024-06-22	no assertion criteria provided	clinical testing	The PALB2 c.3350+5G>A variant is predicted to interfere with splicing. This variant has been reported in the homozygous state in an individual with Fanconi anemia (Mori et al 2019. PubMed ID: 30792206). It has also been described in individuals with breast or pancreatic cancer, and two of these individuals also carried a frameshift variant in ATM (Kondo et al. 2018. PubMed ID: 29731985; Megid et al. 2022. PubMed ID: 36003761; Park et al. 2021. PubMed ID: 34793666). RNA studies indicate this variant causes exon 12 skipping (Mori et al. 2019. PubMed ID: 30792206; Lopez-Perolio et al. 2019. PubMed ID: 30890586; Valenzuela-Palomo et al. 2021. PubMed ID: 34846068). This variant is reported in 0.0058% of alleles in individuals of Latino descent in gnomAD and is interpreted as pathogenic or likely pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/142586/). This variant is interpreted as likely pathogenic.