Submissions for variant NM_024675.4(PALB2):c.321T>G (p.Phe107Leu)

dbSNP: rs781049663

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000706028	SCV000835055	uncertain significance	Familial cancer of breast	2022-07-11	criteria provided, single submitter	clinical testing	This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 107 of the PALB2 protein (p.Phe107Leu). 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 output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The leucine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. ClinVar contains an entry for this variant (Variation ID: 582054). This variant has not been reported in the literature in individuals affected with PALB2-related conditions. This variant is present in population databases (rs781049663, gnomAD 0.003%).
Color Diagnostics, LLC DBA Color Health	RCV001189070	SCV001356273	uncertain significance	Hereditary cancer-predisposing syndrome	2023-12-04	criteria provided, single submitter	clinical testing	This missense variant replaces phenylalanine with leucine at codon 107 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). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with PALB2-related disorders in the literature. This variant has been identified in 1/250952 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.
Baylor Genetics	RCV001825397	SCV002096970	uncertain significance	Fanconi anemia complementation group N	2021-12-21	criteria provided, single submitter	clinical testing	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Ambry Genetics	RCV001189070	SCV002611844	uncertain significance	Hereditary cancer-predisposing syndrome	2022-01-10	criteria provided, single submitter	clinical testing	The p.F107L variant (also known as c.321T>G), located in coding exon 4 of the PALB2 gene, results from a T to G substitution at nucleotide position 321. The phenylalanine at codon 107 is replaced by leucine, 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.