Submissions for variant NM_024675.4(PALB2):c.2176C>T (p.Pro726Ser)

dbSNP: rs566813395

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000197340	SCV000255082	uncertain significance	Familial cancer of breast	2024-02-26	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 726 of the PALB2 protein (p.Pro726Ser). This variant is present in population databases (rs566813395, gnomAD 0.003%). 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: 216744). 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 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.
Ambry Genetics	RCV000569353	SCV000674169	uncertain significance	Hereditary cancer-predisposing syndrome	2023-07-25	criteria provided, single submitter	clinical testing	The c.2176C>T (p.P726S) alteration is located in exon 5 (coding exon 5) of the PALB2 gene. This alteration results from a C to T substitution at nucleotide position 2176, causing the proline (P) at amino acid position 726 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Color Diagnostics, LLC DBA Color Health	RCV000569353	SCV000685927	uncertain significance	Hereditary cancer-predisposing syndrome	2020-12-07	criteria provided, single submitter	clinical testing	This missense variant replaces proline with serine at codon 726 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 hereditary cancer in the literature. This variant has been identified in 1/251488 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.
GeneDx	RCV001775663	SCV002013892	uncertain significance	not provided	2019-06-12	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek et al., 2016); Has not been previously published as pathogenic or benign to our knowledge
Myriad Genetics, Inc.	RCV000197340	SCV004019370	likely benign	Familial cancer of breast	2023-02-09	criteria provided, single submitter	clinical testing	This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752].