Submissions for variant NM_024675.4(PALB2):c.1610C>T (p.Ser537Leu)

gnomAD frequency: 0.00001  dbSNP: rs142103232

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000160871	SCV000211558	uncertain significance	not provided	2022-09-12	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with breast or ovarian cancer (Janatova et al., 2013; Thompson et al., 2015); This variant is associated with the following publications: (PMID: 26283626, 26315354, 24136930, 31600176, Wei2020[article])
Invitae	RCV000168207	SCV000218872	uncertain significance	Familial cancer of breast	2024-01-28	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 537 of the PALB2 protein (p.Ser537Leu). This variant is present in population databases (rs142103232, gnomAD 0.01%). This missense change has been observed in individual(s) with breast cancer (PMID: 26283626). ClinVar contains an entry for this variant (Variation ID: 182791). 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.
Cancer Genetics Laboratory, Peter MacCallum Cancer Centre	RCV000168207	SCV000268002	uncertain significance	Familial cancer of breast	2015-06-01	criteria provided, single submitter	case-control
Ambry Genetics	RCV000220923	SCV000274261	uncertain significance	Hereditary cancer-predisposing syndrome	2023-06-05	criteria provided, single submitter	clinical testing	The p.S537L variant (also known as c.1610C>T), located in coding exon 4 of the PALB2 gene, results from a C to T substitution at nucleotide position 1610. The serine at codon 537 is replaced by leucine, an amino acid with dissimilar properties. This alteration has been reported in 1/999 Australian individuals with breast cancer referred to a familial cancer clinic and in 0/1998 cancer free controls (Thompson ER et al. Breast Cancer Res. 2015; 17(1):111). However, this alteration was also observed in 1/3431 controls in an invasive epithelial ovarian cancer study (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	RCV000220923	SCV000903089	likely benign	Hereditary cancer-predisposing syndrome	2016-11-03	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001121722	SCV001280368	uncertain significance	Fanconi anemia complementation group N	2017-04-28	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000160871	SCV002010980	uncertain significance	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Genetics and Molecular Pathology, SA Pathology	RCV000168207	SCV002761574	uncertain significance	Familial cancer of breast	2020-12-04	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004535051	SCV004116829	uncertain significance	PALB2-related disorder	2023-03-28	criteria provided, single submitter	clinical testing	The PALB2 c.1610C>T variant is predicted to result in the amino acid substitution p.Ser537Leu. This variant has been reported in and individual with breast cancer (Table 3, Thompson et al. 2015. PubMed ID: 26283626). It has also been reported in a control individual from an ovarian cancer cohort study (Table S4, Ramus et al. 2015. PubMed ID: 26315354). This variant is reported in 0.011% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/16-23646257-G-A) and is interpreted as uncertain significance by the vast majority of submitters in ClinVar (https://preview.ncbi.nlm.nih.gov/clinvar/variation/182791/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Leiden Open Variation Database	RCV001030240	SCV001193126	uncertain significance	Carcinoma of colon	2017-01-31	no assertion criteria provided	curation	Curators: Marc Tischkowitz, Arleen D. Auerbach. Submitter to LOVD: Melissa DeRycke.
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000160871	SCV001932663	likely benign	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000160871	SCV001952455	likely benign	not provided		no assertion criteria provided	clinical testing