ClinVar Miner

Submissions for variant NM_024675.4(PALB2):c.3125C>G (p.Thr1042Ser)

gnomAD frequency: 0.00001  dbSNP: rs587780215
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000589774 SCV000150006 uncertain significance not provided 2018-02-23 criteria provided, single submitter clinical testing This variant is denoted PALB2 c.3125C>G at the cDNA level, p.Thr1042Ser (T1042S) at the protein level, and results in the change of a Threonine to a Serine (ACT>AGT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. PALB2 Thr1042Ser was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located within the WD4 repeat region and the region of interaction with BRCA2, RAD51, and POLH that is required for POLH DNA synthesis (Oliver 2009, Buisson 2010, Buisson 2014, UniProt). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether PALB2 Thr1042Ser is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000561324 SCV000665269 uncertain significance Hereditary cancer-predisposing syndrome 2022-10-02 criteria provided, single submitter clinical testing The p.T1042S variant (also known as c.3125C>G), located in coding exon 11 of the PALB2 gene, results from a C to G substitution at nucleotide position 3125. The threonine at codon 1042 is replaced by serine, an amino acid with similar 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. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000589774 SCV000699584 uncertain significance not provided 2017-08-21 criteria provided, single submitter clinical testing Variant summary: The PALB2 c.3125C>G (p.Thr1042Ser) variant involves the alteration of a conserved nucleotide. 4/4 in silico tools predict a benign outcome for this variant . This variant was found in 1/109874 control chromosomes at a frequency of 0.0000091, which does not exceed the estimated maximal expected allele frequency of a pathogenic PALB2 variant (0.0001563). In addition, one clinical diagnostic laboratory has classified this variant as one of uncertain significance. The variant of interest has not, to our knowledge, been reported in affected individuals via publications nor evaluated for functional impact by in vivo/vitro studies. Because of the absence of clinical information and the lack of functional studies, the variant is classified as a variant of uncertain significance (VUS) until additional information becomes available.
Labcorp Genetics (formerly Invitae), Labcorp RCV000706273 SCV000835313 uncertain significance Familial cancer of breast 2023-11-08 criteria provided, single submitter clinical testing This sequence change replaces threonine, which is neutral and polar, with serine, which is neutral and polar, at codon 1042 of the PALB2 protein (p.Thr1042Ser). This variant is present in population databases (rs587780215, gnomAD 0.007%). This variant has not been reported in the literature in individuals affected with PALB2-related conditions. ClinVar contains an entry for this variant (Variation ID: 128137). 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.
Baylor Genetics RCV000706273 SCV004202615 uncertain significance Familial cancer of breast 2024-02-29 criteria provided, single submitter clinical testing

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