ClinVar Miner

Submissions for variant NM_007194.4(CHEK2):c.1357G>C (p.Ala453Pro)

gnomAD frequency: 0.00001  dbSNP: rs763395924
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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000215992 SCV000276026 uncertain significance Hereditary cancer-predisposing syndrome 2020-09-29 criteria provided, single submitter clinical testing The p.A453P variant (also known as c.1357G>C), located in coding exon 11 of the CHEK2 gene, results from a G to C substitution at nucleotide position 1357. The alanine at codon 453 is replaced by proline, an amino acid with highly similar properties. This alteration was observed in with an allele frequency of 0.002 in 7,051 unselected female breast cancer patients and was observed with an allele frequency of 0.0008 in 11,241 female controls of Japanese ancestry. In addition, it was not observed in unselected male breast cancer patients and was observed with an allele frequency of 0.0004 in 12490 male controls of Japanese ancestry​​ (Momozawa Y et al. Nat Commun, 2018 10;9:4083). This amino acid position is not 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.
GeneDx RCV000223343 SCV000279557 uncertain significance not provided 2022-05-14 criteria provided, single submitter clinical testing Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with breast or ovarian cancer but also in unaffected controls (Momozawa 2018, Stuttgen 2019, Choi 2020); This variant is associated with the following publications: (PMID: 32566746, 22419737, 19782031, 30287823, 32019284, 31465090)
Invitae RCV000535584 SCV000633127 uncertain significance Familial cancer of breast 2021-12-17 criteria provided, single submitter clinical testing This sequence change replaces alanine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 453 of the CHEK2 protein (p.Ala453Pro). This variant is present in population databases (rs763395924, gnomAD 0.02%). This missense change has been observed in individual(s) with breast cancer (PMID: 30287823, 31465090). This variant is also known as c.1486G>C p.Ala496Pro. ClinVar contains an entry for this variant (Variation ID: 232008). 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. 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 Diagnostics, LLC DBA Color Health RCV000215992 SCV000689650 uncertain significance Hereditary cancer-predisposing syndrome 2020-08-04 criteria provided, single submitter clinical testing This missense variant replaces alanine with proline at codon 453 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). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has been reported in individuals affected with breast cancer in the literature (PMID: 30287823) and in control individuals (PMID: 30287823). This variant has been identified in 3/251054 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000780185 SCV000917239 likely benign not specified 2020-09-22 criteria provided, single submitter clinical testing Variant summary: CHEK2 c.1357G>C (p.Ala453Pro, also known as c.1486G>C, p.Ala496Pro in the literature) results in a non-conservative amino acid change located in the Protein kinase domain (IPR000719) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 6.3e-05 in 299588 control chromosomes (gnomAD and literature). Within the large gnomAD data set, the variant was found exclusively within the East Asian subpopulation at a frequency of 0.00016 . In exclusively Japanese controls reported by Momozawa_2018 and HGVD-Kyoto (total of 48534 chromosomes), the variant was found at a frequency of 0.00033, slightly higher than the estimated maximum allele frequency expected for a pathogenic variant in CHEK2 (0.00031), suggesting that this variant may be a benign polymorphism found primarily in individuals of Japanese ancestry. c.1357G>C has been reported in the literature in individuals affected with breast and ovarian cancers (e.g. Momozawa_2018, Choi_2020), but also healthy controls (Momozawa_2018). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. In a large Japanese case-control study, the authors found no association with female breast cancer (Momozawa_2018). Co-occurrences with other pathogenic variants have been reported (BRCA1 c.3020delC, p.Ser1007X, Choi_2000; BRCA2 c.5576_5579delTTAA, p.Ile1859LysfsX3, internal sample), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories cited the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign.
Cancer Genomics Group,Japanese Foundation For Cancer Research RCV001030621 SCV001193555 uncertain significance Hereditary breast ovarian cancer syndrome 2019-05-01 criteria provided, single submitter research
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000223343 SCV001470301 uncertain significance not provided 2020-07-16 criteria provided, single submitter clinical testing
Genetic Services Laboratory,University of Chicago RCV000780185 SCV002068437 uncertain significance not specified 2018-02-23 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001355832 SCV001550832 uncertain significance Malignant tumor of breast no assertion criteria provided clinical testing The CHEK2 p.Ala453Pro variant was not identified in the literature nor was it identified in the Cosmic, MutDB, or Zhejiang Colon Cancer Database. The variant was identified in the following databases: dbSNP (ID: rs763395924) as “With Uncertain significance allele”, ClinVar (classified as uncertain significance by Ambry Genetics, GeneDx, Invitae, Color Genomics), and Clinvitae. The variant was identified in control databases in 3 of 245854 chromosomes at a frequency of 0.00001 (Genome Aggregation Database Feb 27, 2017). It was observed in the following population: East Asian in 3 of 17248 chromosomes (freq: 0.0002); while it was not observed in the African, Other, Latino, European, Ashkenazi Jewish, Finnish, and South Asian populations. This variant is located in the kinase domain of CHEK2 and substitutions in the kinase domain have been shown to abolish protein activity (Desrichard 2011, Roeb 2012). The p.Ala453 residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.

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