Submissions for variant NM_024675.4(PALB2):c.48G>A (p.Lys16=)

dbSNP: rs587776405

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000566830	SCV000665419	likely pathogenic	Hereditary cancer-predisposing syndrome	2017-09-15	criteria provided, single submitter	clinical testing	The c.48G>A variant (also known as p.K16K), located in coding exon 1 of the PALB2 gene, results from a G to A substitution at nucleotide position 48. This nucleotide substitution does not change the amino acid at codon 16. However, this change occurs in the last base pair of coding exon 1, which makes it likely to have some effect on normal mRNA splicing. In one assay using lymphoblastoid cell lines from a patient with the c.48G>A alteration, the canonical donor splice site was abolished and an alternative splice site was used resulting in an aberrant transcript and a premature termination codon. The aberrant transcript was not present in one control, and reportedly absent in additional controls from individuals with mutations in other genes and from blood donors (Catucci I et al. Genet. Med. 2014 Sep;16:688-94). In addition, this alteration has been reported in patients with familial breast cancer (Catucci I et al. Genet. Med. 2014 Sep;16:688-94; Antoniou AC et al. N. Engl. J. Med. 2014 Aug;371:497-506). Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001030105	SCV001229787	pathogenic	Familial cancer of breast	2022-09-26	criteria provided, single submitter	clinical testing	This variant is not present in population databases (gnomAD no frequency). This sequence change affects codon 16 of the PALB2 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the PALB2 protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. This variant has been observed in individual(s) with breast cancer (PMID: 24556926). ClinVar contains an entry for this variant (Variation ID: 143978). 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 activation of cryptic splice sites and introduces a premature termination codon (PMID: 24556926; Invitae). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV000566830	SCV001354215	likely pathogenic	Hereditary cancer-predisposing syndrome	2019-11-27	criteria provided, single submitter	clinical testing	This variant causes a G>A nucleotide substitution at the last position of exon 1 of the PALB2 gene. Splice site prediction tools suggest that this variant may impact RNA splicing. Functional RNA studies have shown that this variant causes loss of the canonical donor site of intron 1, resulting in use of an upstream cryptic donor site and a transcript that lacks 17 nucleotides at the 3′ end of exon 1. At the protein level this is expected to result in a frameshift and loss of protein function (p.Cys11fs). This variant has been reported in an individual affected with hereditary breast cancer in the literature (PMID 24556926, 25099575). 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. Based on the available evidence, this variant is classified as Likely Pathogenic.
Department of Molecular Diagnostics, Institute of Oncology Ljubljana	RCV001030105	SCV001499698	pathogenic	Familial cancer of breast	2020-04-02	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV001030105	SCV004188435	likely pathogenic	Familial cancer of breast	2023-09-06	criteria provided, single submitter	clinical testing	This variant is considered likely pathogenic. mRNA analysis has demonstrated abnormal mRNA splicing occurs [PMID: 24556926].
Juno Genomics, Hangzhou Juno Genomics, Inc	RCV004796039	SCV005415956	likely pathogenic	Familial cancer of breast; Fanconi anemia complementation group N; Pancreatic cancer, susceptibility to, 3		criteria provided, single submitter	clinical testing	PS3+PS4_Supporting+PM2_Supporting
SNPedia	RCV000133492	SCV000188566	pathogenic	not provided		no assertion criteria provided	not provided	Converted during submission to Pathogenic.
Leiden Open Variation Database	RCV001030105	SCV001192905	pathogenic	Familial cancer of breast	2019-05-13	no assertion criteria provided	curation	Curators: Marc Tischkowitz, Arleen D. Auerbach. Submitter to LOVD: Marc Tischkowitz.