ClinVar Miner

Submissions for variant NM_024675.3(PALB2):c.3307G>C (p.Val1103Leu) (rs201657283)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000130728 SCV000185617 uncertain significance Hereditary cancer-predisposing syndrome 2018-06-21 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Invitae RCV000226292 SCV000290871 uncertain significance Familial cancer of breast 2019-12-23 criteria provided, single submitter clinical testing This sequence change replaces valine with leucine at codon 1103 of the PALB2 protein (p.Val1103Leu). The valine residue is moderately conserved and there is a small physicochemical difference between valine and leucine. This variant is present in population databases (rs201657283, ExAC 0.01%). This variant has been reported in a study of genetic variants associated with increased risk of breast cancer. However, it is unclear if it was observed in breast cancer cases or controls (PMID: 28779002). ClinVar contains an entry for this variant (Variation ID: 141974). 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 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.
GeneDx RCV000483048 SCV000567970 uncertain significance not provided 2018-10-02 criteria provided, single submitter clinical testing This variant is denoted PALB2 c.3307G>C at the cDNA level, p.Val1103Leu (V1103L) at the protein level, and results in the change of a Valine to a Leucine (GTG>CTG). This variant was observed in 2/13,087 breast cancer cases and in 1/5,488 controls (Decker 2017). PALB2 Val1103Leu was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located within the region required for interaction with POLH and POLH DNA synthesis stimulation (Buisson 2014). 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 Val1103Leu is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Color RCV000130728 SCV000686029 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-09 criteria provided, single submitter clinical testing
Counsyl RCV000226292 SCV000785729 uncertain significance Familial cancer of breast 2017-11-09 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000764042 SCV000894996 uncertain significance Familial cancer of breast; Fanconi anemia, complementation group N; Pancreatic cancer 3 2018-10-31 criteria provided, single submitter clinical testing

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