Submissions for variant NM_024675.4(PALB2):c.2586G>C (p.Lys862Asn)

gnomAD frequency: 0.00001  dbSNP: rs876658279

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000217255	SCV000273307	uncertain significance	Hereditary cancer-predisposing syndrome	2019-12-19	criteria provided, single submitter	clinical testing	The p.K862N variant (also known as c.2586G>C), located in coding exon 6 of the PALB2 gene, results from a G to C substitution at nucleotide position 2586. The lysine at codon 862 is replaced by asparagine, an amino acid with similar properties. However, this change occurs in the last base pair of coding exon 6, which makes it likely to have some effect on normal mRNA splicing. This amino acid position is highly conserved in available vertebrate species. Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to weaken the efficiency of the native splice donor site; however, direct evidence is unavailable. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Color Diagnostics, LLC DBA Color Health	RCV000217255	SCV000690862	uncertain significance	Hereditary cancer-predisposing syndrome	2022-08-29	criteria provided, single submitter	clinical testing	This missense variant replaces lysine with asparagine at codon 862 of the PALB2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). In addition, this variant alters a conserved, last nucleotide c.G of exon 6 and is predicted to impair RNA splicing. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with ovarian cancer (PMID: 32546565). This variant has been identified in 1/251152 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000635942	SCV000757369	uncertain significance	Familial cancer of breast	2023-05-26	criteria provided, single submitter	clinical testing	An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 229932). This missense change has been observed in individual(s) with ovarian cancer (PMID: 32546565). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change replaces lysine, which is basic and polar, with asparagine, which is neutral and polar, at codon 862 of the PALB2 protein (p.Lys862Asn). This variant also falls at the last nucleotide of exon 6, which is part of the consensus splice site for this exon. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003150118	SCV003838085	uncertain significance	Breast and/or ovarian cancer	2022-05-02	criteria provided, single submitter	clinical testing