Submissions for variant NM_024675.4(PALB2):c.1399G>A (p.Gly467Ser)

dbSNP: rs45602239

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000484965	SCV000570930	uncertain significance	not provided	2016-07-13	criteria provided, single submitter	clinical testing	This variant is denoted PALB2 c.1399G>A at the cDNA level, p.Gly467Ser (G467S) at the protein level, and results in the change of a Glycine to a Serine (GGC>AGC). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. PALB2 Gly467Ser was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Glycine and Serine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. PALB2 Gly467Ser occurs at a position that is not conserved 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 evidence, it is unclear whether PALB2 Gly467Ser is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics	RCV001011366	SCV001171676	uncertain significance	Hereditary cancer-predisposing syndrome	2023-05-26	criteria provided, single submitter	clinical testing	The p.G467S variant (also known as c.1399G>A), located in coding exon 4 of the PALB2 gene, results from a G to A substitution at nucleotide position 1399. The glycine at codon 467 is replaced by serine, an amino acid with similar properties. This amino acid position is poorly 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	RCV001220144	SCV001392120	uncertain significance	Familial cancer of breast	2021-04-11	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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with PALB2-related disease. ClinVar contains an entry for this variant (Variation ID: 421651). This variant is not present in population databases (ExAC no frequency). This sequence change replaces glycine with serine at codon 467 of the PALB2 protein (p.Gly467Ser). The glycine residue is weakly conserved and there is a small physicochemical difference between glycine and serine.
Leiden Open Variation Database	RCV001030223	SCV001193098	uncertain significance	Carcinoma of colon	2017-01-31	no assertion criteria provided	curation	Curators: Marc Tischkowitz, Arleen D. Auerbach. Submitter to LOVD: Melissa DeRycke.