Submissions for variant NM_024675.4(PALB2):c.1748T>C (p.Leu583Ser)

dbSNP: rs587782151

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000166198	SCV000216976	uncertain significance	Hereditary cancer-predisposing syndrome	2023-04-04	criteria provided, single submitter	clinical testing	The p.L583S variant (also known as c.1748T>C), located in coding exon 5 of the PALB2 gene, results from a T to C substitution at nucleotide position 1748. The leucine at codon 583 is replaced by serine, an amino acid with dissimilar 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	RCV000464125	SCV000550765	uncertain significance	Familial cancer of breast	2025-01-25	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 583 of the PALB2 protein (p.Leu583Ser). This variant is present in population databases (rs587782151, gnomAD 0.0009%). This variant has not been reported in the literature in individuals affected with PALB2-related conditions. ClinVar contains an entry for this variant (Variation ID: 186581). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt PALB2 protein function with a negative predictive value of 80%. 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.
Color Diagnostics, LLC DBA Color Health	RCV000166198	SCV000685899	uncertain significance	Hereditary cancer-predisposing syndrome	2022-01-20	criteria provided, single submitter	clinical testing	This missense variant replaces leucine with serine at codon 583 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. In a large breast cancer case-control study, this variant has been observed in 3/60463 cases and 4/53457 controls; OR=0.663 (95%CI 0.148 to 2.963) (PMID: 33471991 - Leiden Open Variation Database DB-ID PALB2_010652). This variant has also been reported in 2/6385 cases and 1/6115 controls in an ovarian cancer case-control study (PMID: 32546565). This variant has been identified in 1/250554 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.
CeGaT Center for Human Genetics Tuebingen	RCV000996241	SCV001150870	uncertain significance	not provided	2019-03-01	criteria provided, single submitter	clinical testing
GeneDx	RCV000996241	SCV002818810	uncertain significance	not provided	2023-01-03	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Fulgent Genetics, Fulgent Genetics	RCV005016500	SCV005646488	uncertain significance	Fanconi anemia complementation group N; Pancreatic cancer, susceptibility to, 3; Breast-ovarian cancer, familial, susceptibility to, 5	2024-01-23	criteria provided, single submitter	clinical testing