ClinVar Miner

Submissions for variant NM_024675.4(PALB2):c.2869A>C (p.Lys957Gln) (rs515726103)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000212818 SCV000211525 uncertain significance not provided 2018-02-23 criteria provided, single submitter clinical testing This variant is denoted PALB2 c.2869A>C at the cDNA level, p.Lys957Gln (K957Q) at the protein level, and results in the change of a Lysine to a Glutamine (AAG>CAG). This variant was observed in at least two individuals with breast cancer (Tischkowitz 2012, Kluska 2017). PALB2 Lys957Gln was not observed at a significant allele frequency in large population cohorts (Lek 2016). PALB2 Lys957Gln is located within the WD2 repeat region as well as regions responsible for POLH DNA synthesis stimulation and interaction with POLH, RAD51 and BRCA2 (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 information, it is unclear whether PALB2 Lys957Gln is pathogenic or benign. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000160848 SCV000215397 uncertain significance Hereditary cancer-predisposing syndrome 2018-11-08 criteria provided, single submitter clinical testing In silico models in agreement (benign);Rarity in general population databases (dbsnp, esp, 1000 genomes);Insufficient or conflicting evidence
Invitae RCV000114573 SCV000255092 uncertain significance Familial cancer of breast 2019-12-19 criteria provided, single submitter clinical testing This sequence change replaces lysine with glutamine at codon 957 of the PALB2 protein (p.Lys957Gln). The lysine residue is moderately conserved and there is a small physicochemical difference between lysine and glutamine. This variant is present in population databases (rs515726103, ExAC 0.005%). This variant has been reported in an individual affected with contralateral breast cancer (PMID: 22241545). ClinVar contains an entry for this variant (Variation ID: 126694). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies. 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.
Mendelics RCV000160848 SCV000839011 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-02 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000764046 SCV000895000 uncertain significance Familial cancer of breast; Fanconi anemia, complementation group N; Pancreatic cancer 3 2018-10-31 criteria provided, single submitter clinical testing
Color RCV000160848 SCV000911945 uncertain significance Hereditary cancer-predisposing syndrome 2018-06-11 criteria provided, single submitter clinical testing
Leiden Open Variation Database RCV000114573 SCV001193308 uncertain significance Familial cancer of breast 2019-12-04 no assertion criteria provided curation Curators: Marc Tischkowitz, Arleen D. Auerbach. Submitters to LOVD: Andreas Laner, Marc Tischkowitz.

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