Submissions for variant NM_024675.4(PALB2):c.1727G>A (p.Ser576Asn)

dbSNP: rs879253907

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000236534	SCV000292759	uncertain significance	not provided	2016-02-22	criteria provided, single submitter	clinical testing	This variant is denoted PALB2 c.1727G>A at the cDNA level, p.Ser576Asn (S576N) at the protein level, and results in the change of a Serine to an Asparagine (AGT>AAT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. PALB2 Ser576Asn 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 Serine and Asparagine share similar properties, this is considered a conservative amino acid substitution. PALB2 Ser576Asn occurs at a position that is not conserved and is located within the DNA-binding domain (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 Ser576Asn is pathogenic or benign. We consider it to be a variant of uncertain significance.
Color Diagnostics, LLC DBA Color Health	RCV000772053	SCV000905079	uncertain significance	Hereditary cancer-predisposing syndrome	2018-08-30	criteria provided, single submitter	clinical testing
Invitae	RCV001317387	SCV001508046	uncertain significance	Familial cancer of breast	2023-02-03	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 576 of the PALB2 protein (p.Ser576Asn). 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: 245702). 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).