ClinVar Miner

Submissions for variant NM_024675.4(PALB2):c.2897T>C (p.Ile966Thr) (rs587780214)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000212819 SCV000150003 uncertain significance not provided 2017-10-31 criteria provided, single submitter clinical testing This variant is denoted PALB2 c.2897T>C at the cDNA level, p.Ile966Thr (I966T) at the protein level, and results in the change of an Isoleucine to a Threonine (ATA>ACA). This variant was observed in an individual with a personal history of bilateral triple negative breast, endometrial and colon cancer who was also found to harbor an MLH1 variant. Familial testing was completed and showed that the MLH1 variant appeared to segregate to the side of the family reported to have several Lynch syndrome-related cancers while PALB2 Ile966Thr did not (Ollier 2015). PALB2 Ile966Thr was also identified in at least one other individual with a personal and/or family history of breast cancer (Nguyen-Dumont 2015). PALB2 Ile966Thr was not observed at a significant allele frequency in large population cohorts (Lek 2016). Since Isoleucine and Threonine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. PALB2 Ile966Thr occurs at a position that is conserved across species and is located in the WD3 repeat, a region required for interaction with POLH and POLH DNA synthesis stimulation, and a region of interaction with RAD51, BRCA2 and POLH (UniProt). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, it is unclear whether PALB2 Ile966Thr is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000116094 SCV000216349 uncertain significance Hereditary cancer-predisposing syndrome 2018-03-22 criteria provided, single submitter clinical testing Insufficient evidence
Invitae RCV000204848 SCV000261308 uncertain significance Familial cancer of breast 2019-12-26 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with threonine at codon 966 of the PALB2 protein (p.Ile966Thr). The isoleucine residue is highly conserved and there is a moderate physicochemical difference between isoleucine and threonine. This variant is present in population databases (rs587780214, ExAC 0.003%). This variant has been reported in several individuals affected with a personal and/or family history of breast cancer (PMID: 25575445, 26328243). ClinVar contains an entry for this variant (Variation ID: 128136). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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.
Color RCV000116094 SCV000685988 uncertain significance Hereditary cancer-predisposing syndrome 2020-01-22 criteria provided, single submitter clinical testing
Counsyl RCV000204848 SCV000784956 uncertain significance Familial cancer of breast 2017-02-17 criteria provided, single submitter clinical testing
Mendelics RCV000116094 SCV000839010 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-02 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000212819 SCV000889590 uncertain significance not provided 2017-12-26 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000764045 SCV000894999 uncertain significance Familial cancer of breast; Fanconi anemia, complementation group N; Pancreatic cancer 3 2018-10-31 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000212819 SCV001245835 uncertain significance not provided 2020-01-01 criteria provided, single submitter clinical testing
Molecular Oncology Laboratory,Centre Jean Perrin RCV000202384 SCV000257398 association Triple-negative breast cancer 2015-02-26 no assertion criteria provided case-control PALB2 protein absent in tumor tissue (IHC)
Leiden Open Variation Database RCV000212819 SCV001193311 uncertain significance not provided 2019-12-04 no assertion criteria provided curation Curators: Marc Tischkowitz, Arleen D. Auerbach. Submitter to LOVD: Andreas Laner.

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