ClinVar Miner

Submissions for variant NM_007194.4(CHEK2):c.480A>G (p.Ile160Met) (rs575910805)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000116020 SCV000186249 uncertain significance Hereditary cancer-predisposing syndrome 2017-06-13 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence,In silico models in agreement (deleterious) and/or completely conserved position in appropriate species
Color RCV000116020 SCV000684649 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-01 criteria provided, single submitter clinical testing
GeneDx RCV000586231 SCV000149929 uncertain significance not provided 2018-10-11 criteria provided, single submitter clinical testing This variant is denoted CHEK2 c.480A>G at the cDNA level, p.Ile160Met (I160M) at the protein level, and results in the change of an Isoleucine to a Methionine (ATA>ATG). This variant has been shown to have a partial response to DNA damage in an in vivo functional assay (Roeb 2012). CHEK2 Ile160Met has been observed in individuals with breast and/or ovarian cancer (Dufault 2004, Mohamad 2015, Maxwell 2016). One breast cancer patient was from a large family harboring another CHEK2 variant of uncertain significance in trans, making segregation studies uninformative (Roeb 2012). CHEK2 Ile160Met was observed at an allele frequency of 0.08% (24/30782) in individuals of South Asian ancestry in large population cohorts (Lek 2016). This variant is located in the FHA domain (Cai 2009, Roeb 2012). 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 CHEK2 Ile160Met is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
GeneKor MSA RCV000116020 SCV000822001 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-01 criteria provided, single submitter clinical testing
Genomic Research Center,Shahid Beheshti University of Medical Sciences RCV000790910 SCV000930157 uncertain significance CHEK2-Related Cancer Susceptibility 2019-04-27 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000586231 SCV000698806 uncertain significance not provided 2017-05-23 criteria provided, single submitter clinical testing Variant summary: The CHEK2 c.480A>G (p.Ile160Met) variant involves the alteration of a non-conserved nucleotide but is located in forkhead-associated (FHA) domain of the protein. Since the p.I160M variant is located in the forkhead-associated (FHA) domain of the CHEK2 protein, which is important for dynamic interactions between upstream regulators or downstream targets of the CHEK2, this variant could lead to the deregulation of CHEK2 or structural abnormalities which may hinder protein-protein interactions (Mohamad_2015). 3/4 in silico tools predict a damaging outcome for this variant. This variant was found in 21/122538 control chromosomes including ExAC, predominantly observed in the South Asian subpopulation at a frequency of 0.0010297 (17/16510). This frequency is about 3 times the estimated maximal expected allele frequency of a pathogenic CHEK2 variant (0.0003125), suggesting this is possibly a benign polymorphism found primarily in the populations of South Asian origin. However, this variant has also been found in multiple patients/families with breast cancer and was not found in 500 controls aged over 50 (Dufault_2004, Roeb_2012, Fostira _2013, Mohamad_2015). In a family, two female relatives with breast cancer diagnoses at ages 38 and 42 years were compound heterozygotes for this variant and p.G167R; three as-yet-unaffected sisters are heterozygous for only one or the other of the two alleles (Roeb_2012). CHEK2 p.I160M was inherited from the father who had a diagnosis of breast cancer, but this allele was also present his elderly unaffected sister (age 96). CHEK2 p.G167R was inherited from the mother who died of non-Hodgkins lymphoma. Based on pedigree considerations alone, it was not possible to determine which allele(s) were damaging. In a small case-control cohort, CHEK2 p.I160M variant was found in 2/172 (1.16%) unselected invasive breast cancer patients (Indians) and 1/90 (1.11%) Indian controls (Mohamad_2015), suggesting that this variant may not predispose to a higher risk of breast cancer in Indian population. A Functional study showed that this variant maintains about 50% activity in DNA damage response (Roeb_2012). While two clinical diagnostic laboratories/ have classified this variant as uncertain significance, one has classified as likely benign. A recent study also classified this variant as likely benign using ACMG guideline (Maxwell_2016). Although this variant has been reported in multiple HBOC patients and functional study suggests it may lose some activity, the relative high frequency in control population supports that this variant is unlikely associated with HBOC. Thus, it is classified as VUS-possibly benign.
Invitae RCV000199707 SCV000253486 likely benign Familial cancer of breast 2017-12-29 criteria provided, single submitter clinical testing

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