Submissions for variant NM_024675.4(PALB2):c.2353C>T (p.Pro785Ser)

dbSNP: rs730881889

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000160842	SCV000211517	uncertain significance	not provided	2016-03-02	criteria provided, single submitter	clinical testing	This variant is denoted PALB2 c.2353C>T at the cDNA level, p.Pro785Ser (P785S) at the protein level, and results in the change of a Proline to a Serine (CCA>TCA). This variant has been observed in one individual with serous ovarian cancer and no controls (Ramus 2015). PALB2 Pro785Ser 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 Proline and Serine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. PALB2 Pro785Ser occurs at a position that is not conserved and is located within the domain required for interaction with POLH and POLH DNA synthesis stimulation (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 Pro785Ser is pathogenic or benign. We consider it to be a variant of uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000460019	SCV000550670	uncertain significance	Familial cancer of breast	2024-12-09	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 785 of the PALB2 protein (p.Pro785Ser). This variant is present in population databases (rs730881889, gnomAD 0.0009%). This missense change has been observed in individual(s) with ovarian cancer (PMID: 26315354). ClinVar contains an entry for this variant (Variation ID: 182768). 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.
Counsyl	RCV000460019	SCV000786222	uncertain significance	Familial cancer of breast	2018-03-23	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV001015124	SCV001175924	uncertain significance	Hereditary cancer-predisposing syndrome	2023-04-18	criteria provided, single submitter	clinical testing	The p.P785S variant (also known as c.2353C>T), located in coding exon 5 of the PALB2 gene, results from a C to T substitution at nucleotide position 2353. The proline at codon 785 is replaced by serine, an amino acid with similar properties. In one study, this alteration was observed in 1/3236 cases with invasive epithelial ovarian cancer and 0/3431 controls (Ramus SJ et al. J. Natl. Cancer Inst., 2015 Nov;107:). 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.
Color Diagnostics, LLC DBA Color Health	RCV001015124	SCV001345096	uncertain significance	Hereditary cancer-predisposing syndrome	2018-12-06	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000460019	SCV004019201	uncertain significance	Familial cancer of breast	2023-03-30	criteria provided, single submitter	clinical testing	This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.
Mendelics	RCV004700497	SCV005205570	likely benign	Hereditary cancer	2024-09-11	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following: it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease, and/or has normal protein function, and/or has lack of segregation with disease, and/or has been detected in co-occurrence with known pathogenic variant, and/or has lack of disease association in case-control studies, and/or is located in a region inconsistent with a known cause of pathogenicity.