Submissions for variant NM_024675.4(PALB2):c.191C>T (p.Ser64Leu)

dbSNP: rs1567223942

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Color Diagnostics, LLC DBA Color Health	RCV000775864	SCV000910339	uncertain significance	Hereditary cancer-predisposing syndrome	2019-02-13	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001297469	SCV001486484	uncertain significance	Familial cancer of breast	2022-12-01	criteria provided, single submitter	clinical testing	Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The leucine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect 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. Experimental studies have shown that this missense change affects PALB2 function (PMID: 33169439). ClinVar contains an entry for this variant (Variation ID: 630469). This missense change has been observed in individual(s) with pancreatic cancer (PMID: 33169439). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 64 of the PALB2 protein (p.Ser64Leu).
Mendelics	RCV003492169	SCV002517351	uncertain significance	Hereditary cancer	2024-01-23	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004527778	SCV004112200	uncertain significance	PALB2-related disorder	2023-04-27	criteria provided, single submitter	clinical testing	The PALB2 c.191C>T variant is predicted to result in the amino acid substitution p.Ser64Leu. This variant has been reported in an individual with familial pancreatic cancer (Zhang et al. 2021. PubMed ID: 33169439). In vitro experimental studies suggest this variant impacts PALB2 DNA damage responses, but does not impact PALB2 protein-protein interactions (Zhang et al. 2021. PubMed ID: 33169439). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. It has conflicting interpretations of likely pathogenic and uncertain significance in ClinVar (https://preview.ncbi.nlm.nih.gov/clinvar/variation/630469/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Baylor Genetics	RCV001297469	SCV004202610	uncertain significance	Familial cancer of breast	2023-11-17	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000775864	SCV005029070	uncertain significance	Hereditary cancer-predisposing syndrome	2023-12-06	criteria provided, single submitter	clinical testing	The p.S64L variant (also known as c.191C>T), located in coding exon 3 of the PALB2 gene, results from a C to T substitution at nucleotide position 191. The serine at codon 64 is replaced by leucine, an amino acid with dissimilar properties. This alteration was identified in an individual with a personal and family history of pancreatic cancer (Zhang Y et al. Hum Mutat, 2021 Feb;42:150-163). Functional studies showed reduced recruitment of PALB2 and RAD51 to nuclear foci and reduced HR activity (Zhang Y et al. Hum Mutat, 2021 02;42:150-163). 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.