Submissions for variant NM_024675.4(PALB2):c.2606C>G (p.Ser869Cys)

dbSNP: rs779279139

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Cancer Genetics Laboratory, Peter MacCallum Cancer Centre	RCV000211067	SCV000268015	uncertain significance	Familial cancer of breast	2015-06-01	criteria provided, single submitter	case-control
Invitae	RCV000211067	SCV000550712	uncertain significance	Familial cancer of breast	2023-12-18	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 869 of the PALB2 protein (p.Ser869Cys). This variant is present in population databases (rs779279139, gnomAD 0.004%). This missense change has been observed in individual(s) with breast and/or ovarian cancer (PMID: 26283626, 26315354, 26564480, 30303537). ClinVar contains an entry for this variant (Variation ID: 225855). 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 expected to disrupt PALB2 protein function with a positive 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.
GeneDx	RCV000484494	SCV000570143	uncertain significance	not provided	2016-04-29	criteria provided, single submitter	clinical testing	This variant is denoted PALB2 c.2606C>G at the cDNA level, p.Ser869Cys (S869C) at the protein level, and results in the change of a Serine to a Cysteine (TCC>TGC). This variant was observed in at least two patients with familial breast cancer (Damiola 2015, Thompson 2015). PALB2 Ser869Cys 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 Serine and Cysteine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. PALB2 Ser869Cys occurs at a position that is not conserved and is located within the WD1 repeat as well as the region of interaction with RAD51, BRCA2 and POLH that is required for interaction with POLH and POLH DNA synthesis stimulation (UniProt). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether PALB2 Ser869Cys is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics	RCV000574296	SCV000663305	uncertain significance	Hereditary cancer-predisposing syndrome	2023-05-02	criteria provided, single submitter	clinical testing	The p.S869C variant (also known as c.2606C>G), located in coding exon 7 of the PALB2 gene, results from a C to G substitution at nucleotide position 2606. The serine at codon 869 is replaced by cysteine, an amino acid with dissimilar properties. This variant has been reported in several cohorts of patients with personal and/or family histories of breast cancer (Thompson ER et al. Breast Cancer Res. 2015; 17(1):111; Decker B et al. J Med Genet, 2017 11;54:732-741; Damiola F et al. Breast Cancer Res. Treat. 2015 Dec; 154(3):463-71; Girard E et al. Int J Cancer, 2019 04;144:1962-1974). This alteration was also observed in 1/3236 cases with invasive epithelial ovarian cancer and in 0/3431 controls (Ramus SJ et al. J Natl Cancer Inst, 2015 Nov;107). This amino acid position is 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.
Color Diagnostics, LLC DBA Color Health	RCV000574296	SCV001339503	uncertain significance	Hereditary cancer-predisposing syndrome	2022-10-18	criteria provided, single submitter	clinical testing	This missense variant replaces serine with cysteine at codon 869 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 been reported in individuals affected with breast or ovarian cancer (PMID: 26283626, 26315354, 26564480, 30303537) and in an unaffected individual (PMID: 32546565), and this variant also has been reported in a breast cancer case-control meta-analysis in 2/60466 cases and 3/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID PALB2_010869). This variant has also been identified in 2/251482 chromosomes in the general population by the Genome Aggregation Database (gnomAD) and in a control sample (PMID: 32546565). 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.