Submissions for variant NM_024675.4(PALB2):c.1619A>G (p.Asn540Ser)

dbSNP: rs1064793609

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000486906	SCV000566597	uncertain significance	not provided	2015-05-15	criteria provided, single submitter	clinical testing	This variant is denoted PALB2 c.1619A>G at the cDNA level, p.Asn540Ser (N540S) at the protein level, and results in the change of an Asparagine to a Serine (AAC>AGC). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. PALB2 Asn540Ser was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Asparagine and Serine share similar properties, this is considered a conservative amino acid substitution. PALB2 Asn540Ser occurs at a position that is not conserved, with Serine being the naturally occurring amino acid at this position in one species, and is located in the DNA-binding region (UniProt). In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available information, it is unclear whether PALB2 Asn540Ser is pathogenic or benign. We consider it to be a variant of uncertain significance.
Ambry Genetics	RCV002402384	SCV002707343	uncertain significance	Hereditary cancer-predisposing syndrome	2021-02-04	criteria provided, single submitter	clinical testing	The p.N540S variant (also known as c.1619A>G), located in coding exon 4 of the PALB2 gene, results from an A to G substitution at nucleotide position 1619. The asparagine at codon 540 is replaced by serine, an amino acid with highly similar properties. This amino acid position is not well conserved in available vertebrate species. 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV003607289	SCV004536638	uncertain significance	Familial cancer of breast	2023-08-20	criteria provided, single submitter	clinical testing	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. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt PALB2 protein function. ClinVar contains an entry for this variant (Variation ID: 419052). This variant has not been reported in the literature in individuals affected with PALB2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 540 of the PALB2 protein (p.Asn540Ser).