ClinVar Miner

Submissions for variant NM_024675.4(PALB2):c.3014T>C (p.Phe1005Ser)

gnomAD frequency: 0.00001  dbSNP: rs879254268
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000235539 SCV000294023 uncertain significance not provided 2018-02-11 criteria provided, single submitter clinical testing This variant is denoted PALB2 c.3014T>C at the cDNA level, p.Phe1005Ser (F1005S) at the protein level, and results in the change of a Phenylalanine to a Serine (TTT>TCT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. PALB2 Phe1005Ser was not observed in large population cohorts (Lek 2016). PALB2 Phe1005Ser is located in the WD3 repeat region, the region required for POLH DNA synthesis stimulation, and the region of interaction with POLH, RAD51, and BRCA2 (Oliver 2009, Buisson 2010, Buisson 2014, UniProt). In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether PALB2 Phe1005Ser is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000565406 SCV000670674 uncertain significance Hereditary cancer-predisposing syndrome 2023-09-01 criteria provided, single submitter clinical testing The p.F1005S variant (also known as c.3014T>C), located in coding exon 10 of the PALB2 gene, results from a T to C substitution at nucleotide position 3014. The phenylalanine at codon 1005 is replaced by serine, an amino acid with highly dissimilar properties. 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.
Color Diagnostics, LLC DBA Color Health RCV000565406 SCV000690892 uncertain significance Hereditary cancer-predisposing syndrome 2023-12-04 criteria provided, single submitter clinical testing This missense variant replaces phenylalanine with serine at codon 1005 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 not been reported in individuals affected with PALB2-related disorders in the literature. 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 RCV000635611 SCV000757030 uncertain significance Familial cancer of breast 2023-08-08 criteria provided, single submitter clinical testing This variant is not present in population databases (gnomAD no frequency). 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. 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. ClinVar contains an entry for this variant (Variation ID: 246461). This variant has not been reported in the literature in individuals affected with PALB2-related conditions. This sequence change replaces phenylalanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 1005 of the PALB2 protein (p.Phe1005Ser).
Baylor Genetics RCV000635611 SCV004202150 uncertain significance Familial cancer of breast 2023-08-02 criteria provided, single submitter clinical testing

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