Submissions for variant NM_024675.4(PALB2):c.2606C>T (p.Ser869Phe)

gnomAD frequency: 0.00001  dbSNP: rs779279139

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000481486	SCV000569678	uncertain significance	not provided	2017-07-14	criteria provided, single submitter	clinical testing	This variant is denoted PALB2 c.2606C>T at the cDNA level, p.Ser869Phe (S869F) at the protein level, and results in the change of a Serine to a Phenylalanine (TCC>TTC). This variant was observed in an individual with Lynch-syndrome associated cancer and/or polyps (Yurgelun 2015). PALB2 Ser869Phe was not observed in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Serine and Phenylalanine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. PALB2 Ser869Phe occurs at a position that is not conserved, but is located within the WD1 repeat, within the region of interaction with RAD51, BRCA2, and POLH and is required for POLH DNA synthesis stimulation (UniProt). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, it is unclear whether PALB2 Ser869Phe is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Color Diagnostics, LLC DBA Color Health	RCV000580078	SCV000685961	uncertain significance	Hereditary cancer-predisposing syndrome	2021-10-26	criteria provided, single submitter	clinical testing	This missense variant replaces serine with phenylalanine 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 two individuals affected with suspected Lynch syndrome cancers in the literature (PMID: 25980754, 33809179). In a large breast cancer case-control study, this variant was identified in 2/60464 cases and 2/53459 controls (PMID: 33471991 - Leiden Open Variation Database DB-ID PALB2_010868). This variant has not been identified 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000688490	SCV000816105	uncertain significance	Familial cancer of breast	2023-09-08	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 869 of the PALB2 protein (p.Ser869Phe). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of Lynch syndrome (PMID: 25980754). ClinVar contains an entry for this variant (Variation ID: 420725). 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. 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000481486	SCV000889585	uncertain significance	not provided	2017-10-09	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000580078	SCV001176953	uncertain significance	Hereditary cancer-predisposing syndrome	2024-02-07	criteria provided, single submitter	clinical testing	The p.S869F variant (also known as c.2606C>T), located in coding exon 7 of the PALB2 gene, results from a C to T substitution at nucleotide position 2606. The serine at codon 869 is replaced by phenylalanine, an amino acid with highly dissimilar properties. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, the clinical significance of this alteration remains unclear.
Baylor Genetics	RCV000688490	SCV004202197	uncertain significance	Familial cancer of breast	2023-06-21	criteria provided, single submitter	clinical testing