ClinVar Miner

Submissions for variant NM_024675.4(PALB2):c.2752C>T (p.Pro918Ser)

dbSNP: rs515726094
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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000165106 SCV000215816 uncertain significance Hereditary cancer-predisposing syndrome 2023-03-29 criteria provided, single submitter clinical testing The p.P918S variant (also known as c.2752C>T), located in coding exon 8 of the PALB2 gene, results from a C to T substitution at nucleotide position 2752. The proline at codon 918 is replaced by serine, an amino acid with similar properties. This alteration was reported in 4/1144 BRCA1/2 negative breast cancer patients with at least two relatives diagnosed with breast cancer (Casadei S et al. Cancer Res., 2011 Mar;71:2222-9). This alteration has also been reported in at least one subject in a study of 13087 breast cancer cases and 5488 control individuals in the UK (Decker B et al. J Med Genet, 2017 11;54:732-741). Additionally, this alteration was detected in 1/5589 German BRCA1/2-negative probands with breast cancer (Hauke J et al. Cancer Med, 2018 04;7:1349-1358). This alteration was also detected in a high-risk individual undergoing pancreatic cancer screening (Abe T et al. J Clin Oncol, 2019 05;37:1070-1080). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp RCV000114556 SCV000255090 uncertain significance Familial cancer of breast 2024-01-09 criteria provided, single submitter clinical testing This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 918 of the PALB2 protein (p.Pro918Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast cancer (PMID: 21285249; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 126679). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on PALB2 protein function. RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (Invitae). 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.
Counsyl RCV000114556 SCV000488007 uncertain significance Familial cancer of breast 2015-12-11 criteria provided, single submitter clinical testing
GeneDx RCV000478088 SCV000566460 uncertain significance not provided 2021-04-28 criteria provided, single submitter clinical testing Not observed in large population cohorts (Lek 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with breast cancer (Casadei 2011, Decker 2017); This variant is associated with the following publications: (PMID: 21285249, 28024868, 28779002, 31843900)
Color Diagnostics, LLC DBA Color Health RCV000165106 SCV000685974 uncertain significance Hereditary cancer-predisposing syndrome 2023-11-08 criteria provided, single submitter clinical testing This missense variant replaces proline with serine at codon 918 of the PALB2 protein. Computational prediction suggests that this variant may not impact protein structure and function. An RNA study has reported that this variant does not impact mRNA splicing (PMID: 31843900). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in at least five individuals affected with breast cancer (PMID: 21285249, 28779002, 29522266) and has been detected in a breast cancer case-control meta-analysis in 2/60466 cases and 0/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID PALB2_010192). 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.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000478088 SCV001469848 uncertain significance not provided 2019-10-18 criteria provided, single submitter clinical testing
Myriad Genetics, Inc. RCV000114556 SCV004019665 likely benign Familial cancer of breast 2023-03-31 criteria provided, single submitter clinical testing This variant is considered likely benign. This variant has been observed in trans with a known pathogenic variant in one or more individuals lacking clinical features consistent with gene-specific recessive disease.
Baylor Genetics RCV000114556 SCV004202116 uncertain significance Familial cancer of breast 2024-03-03 criteria provided, single submitter clinical testing
True Health Diagnostics RCV000165106 SCV000886698 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-13 no assertion criteria provided clinical testing
Leiden Open Variation Database RCV000114556 SCV001193284 uncertain significance Familial cancer of breast 2019-05-13 no assertion criteria provided curation Curators: Marc Tischkowitz, Arleen D. Auerbach. Submitter to LOVD: Marc Tischkowitz.
King Laboratory, University of Washington RCV001171432 SCV001251342 benign not specified 2019-09-01 no assertion criteria provided research

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