ClinVar Miner

Submissions for variant NM_007194.4(CHEK2):c.436A>C (p.Ile146Leu) (rs781678896)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000570860 SCV000661728 uncertain significance Hereditary cancer-predisposing syndrome 2020-09-28 criteria provided, single submitter clinical testing The p.I146L variant (also known as c.436A>C), located in coding exon 2 of the CHEK2 gene, results from an A to C substitution at nucleotide position 436. The isoleucine at codon 146 is replaced by leucine, an amino acid with highly similar properties. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Color Health, Inc RCV000570860 SCV000684639 uncertain significance Hereditary cancer-predisposing syndrome 2020-12-08 criteria provided, single submitter clinical testing This missense variant replaces isoleucine with leucine at codon 146 of the CHEK2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 3/251306 chromosomes 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.
Invitae RCV000635731 SCV000757153 uncertain significance Familial cancer of breast 2020-10-14 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with leucine at codon 146 of the CHEK2 protein (p.Ile146Leu). The isoleucine residue is highly conserved and there is a small physicochemical difference between isoleucine and leucine. This variant is present in population databases (rs781678896, ExAC 0.004%). This variant has not been reported in the literature in individuals with CHEK2-related conditions. ClinVar contains an entry for this variant (Variation ID: 479549). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: Deleterious; PolyPhen-2: Benign; 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.
Fulgent Genetics,Fulgent Genetics RCV000765624 SCV000896949 uncertain significance Familial cancer of breast; Li-Fraumeni syndrome 2; Bone osteosarcoma; Malignant tumor of prostate 2018-10-31 criteria provided, single submitter clinical testing

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