ClinVar Miner

Submissions for variant NM_024675.3(PALB2):c.298C>T (p.Leu100Phe) (rs61756147)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000116095 SCV000172824 uncertain significance Hereditary cancer-predisposing syndrome 2017-07-14 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Cancer Genetics Laboratory,Peter MacCallum Cancer Centre RCV000114577 SCV000267982 uncertain significance Familial cancer of breast 2015-06-01 criteria provided, single submitter case-control
Color RCV000116095 SCV000910613 benign Hereditary cancer-predisposing syndrome 2016-02-17 criteria provided, single submitter clinical testing
GeneDx RCV000212772 SCV000150004 uncertain significance not provided 2018-11-27 criteria provided, single submitter clinical testing This variant is denoted PALB2 c.298C>T at the cDNA level, p.Leu100Phe (L100F) at the protein level, and results in the change of a Leucine to a Phenylalanine (CTT>TTT). This variant has been observed in individuals with breast, ovarian, or pancreatic cancer; however, it has also been identified in healthy controls (Wong 2011, Hartley 2014, Kanchi 2014, Grant 2015, Ramus 2015, Thompson, 2015, Tung 2015, Tung 2016). Additionally, this variant was detected in a multi-ethnic exome array study, but it was not found to have a statistically significant association with breast cancer risk (Haiman 2013). PALB2 Leu100Phe was observed at an allele frequency of 0.03% (42/126,642) in individuals of European ancestry in large population cohorts (Lek 2016). This variant occurs in a region that interacts with BRCA1 and RAD51 (Sy 2009, Buisson 2010). 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 Leu100Phe is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
GenomeConnect, ClinGen RCV000212772 SCV000784703 not provided not provided no assertion provided phenotyping only GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.
Invitae RCV000114577 SCV000166659 uncertain significance Familial cancer of breast 2018-12-28 criteria provided, single submitter clinical testing This sequence change replaces leucine with phenylalanine at codon 100 of the PALB2 protein (p.Leu100Phe). The leucine residue is moderately conserved and there is a small physicochemical difference between leucine and phenylalanine. This variant is present in population databases (rs61756147, ExAC 0.04%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been reported in individuals affected with breast, ovarian, and pancreatic cancer (PMID: 21409391, 25225577, 26315354, 26976419, 28767289). ClinVar contains an entry for this variant (Variation ID: 126698). 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 phenylalanine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.
PALB2 database RCV000114577 SCV000148523 uncertain significance Familial cancer of breast 2012-10-18 no assertion criteria provided literature only
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000212772 SCV000889593 uncertain significance not provided 2018-07-31 criteria provided, single submitter clinical testing
True Health Diagnostics RCV000116095 SCV000805278 likely benign Hereditary cancer-predisposing syndrome 2018-06-18 no assertion criteria provided clinical testing

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