ClinVar Miner

Submissions for variant NM_007194.4(CHEK2):c.1336A>G (p.Asn446Asp) (rs121908705)

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Total submissions: 13
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000114765 SCV000210989 uncertain significance not provided 2018-09-16 criteria provided, single submitter clinical testing This variant is denoted CHEK2 c.1336A>G at the cDNA level, p.Asn446Asp (N446D) at the protein level, and results in the change of an Asparagine to an Aspartic Acid (AAC>GAC). This variant has been observed in at least one individual each with breast cancer, rectal cancer, and non-Hodgkin lymphoma, and in one control individual in a case-control breast cancer study (Le Calvez-Kelm 2011, Havranek 2015, Kraus 2016, Pearlman 2017). Although this variant was observed in large population cohorts, population data in this region of CHEK2 are not considered reliable due to high pseudogene homology (Lek 2016). This variant is located in the kinase 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 Asn446Asp is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000196666 SCV000254924 uncertain significance Familial cancer of breast 2020-10-30 criteria provided, single submitter clinical testing This sequence change replaces asparagine with aspartic acid at codon 446 of the CHEK2 protein (p.Asn446Asp). The asparagine residue is moderately conserved and there is a small physicochemical difference between asparagine and aspartic acid. This variant is present in population databases (rs121908705, ExAC 0.04%). This variant has been observed in individuals affected with non-Hodgkin lymphoma (PMID: 26506619), breast cancer (PMID: 27616075) and rectal cancer (PMID: 27978560). ClinVar contains an entry for this variant (Variation ID: 126909). This variant has been reported not to substantially affect CHEK2 protein function (PMID: 30851065). 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 Health, Inc RCV000449435 SCV000537565 uncertain significance Hereditary cancer-predisposing syndrome 2020-06-29 criteria provided, single submitter clinical testing This missense variant replaces asparagine with aspartic acid at codon 446 of the CHEK2 protein. Computational prediction tool suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). A functional study has reported this variant to be functional for the complementation of yeast rad53-deficient strain in growth after DNA damage (PMID: 30851065). This variant has been reported in individuals affected with breast cancer, colorectal cancer, and non-Hodgkin lymphoma and in an unaffected control from a breast cancer case-control study (PMID: 21244692, 26506619, 27616075, 27978560). This variant has also been identified in 19/282494 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available clinical evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000160437 SCV000601151 uncertain significance not specified 2017-05-10 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000515378 SCV000611452 uncertain significance Familial cancer of breast; Li-Fraumeni syndrome 2; Osteosarcoma; Malignant tumor of prostate 2017-05-23 criteria provided, single submitter clinical testing
Ambry Genetics RCV000449435 SCV000661698 likely benign Hereditary cancer-predisposing syndrome 2020-03-30 criteria provided, single submitter clinical testing Co-occurence with a mutation in another gene that clearly explains a proband's phenotype;In silico models in agreement (benign);Insufficient or conflicting evidence
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000160437 SCV000698771 uncertain significance not specified 2019-10-28 criteria provided, single submitter clinical testing Variant summary: CHEK2 c.1336A>G (p.Asn446Asp) results in a conservative amino acid change located in the Protein kinase domain (IPR000719) of the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 7.5e-05 in 253306 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in CHEK2 causing Hereditary Breast and Ovarian Cancer (7.5e-05 vs 0.00031), allowing no conclusion about variant significance. The variant was reported in breast cancer, colorectal cancer or Non-Hodgkin Lymphoma patients, without strong evidence for causality (Kraus 2016, Havranek 2015, Pearlman 2016), and was also found in healthy controls (Le Calvez-Kelm 2011). These reports however, do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. Co-occurrence with another likely pathogenic variant has been reported in an internal sample (APC c.4873delC, p.Gln1625fsX25). In an in vivo, yeast based functional assay, the variant was classified as benign (Delimitsou_2019). Six other ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly benign until additional evidence becomes available.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000114765 SCV000888102 uncertain significance not provided 2018-06-21 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV001147096 SCV001307874 uncertain significance CHEK2-Related Cancer Susceptibility 2017-04-27 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Institute of Human Genetics, University of Leipzig Medical Center RCV000196666 SCV001429382 uncertain significance Familial cancer of breast 2019-05-06 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000114765 SCV001501836 uncertain significance not provided 2020-09-01 criteria provided, single submitter clinical testing
Institute. of Biochemistry and Experimental Oncology, First Faculty of Medicine, Charles University in Prague RCV000114765 SCV000148660 not provided not provided no assertion provided not provided
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001356532 SCV001551731 uncertain significance Malignant tumor of breast no assertion criteria provided clinical testing The CHEK2 p.Asn446Asp variant was identified in 3 of 10018 proband chromosomes (frequency: 0.0003) from individuals or families with Non-Hodgkin Lymphoma, breast cancer and colorectal cancer (Havranek 2015, Kraus 2017, Le Calvez-Kelm 2011, Pearlman 2017) and was present in 1 of 3208 control chromosomes (frequency: 0.0003) from healthy individuals (Havranek 2015, Le Calvez-Kelm 2011).The variant was also identified in dbSNP (ID: rs121908705) as With Uncertain significance allele, ClinVar (classified as uncertain significance by GeneDx, Invitae, Color Genomics, Ambry Genetics and 3 clinical laboratories), Clinvitae (classified as uncertain significance by Clinvar and Invitae), MutDB, databases. The variant was not identified in Cosmic, Zhejiang Colon Cancer Database, databases. The variant was identified in control databases in 19 of 276858 chromosomes at a frequency of 0.000069 (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include European Non-Finnish in 9 of 126372 chromosomes (freq: 0.0001), and South Asian in 10 of 30776 chromosomes (freq: 0.0003), while the variant was not observed in the African, Other, Latino, Ashkenazi Jewish, East Asian, European Finnish, populations. The p.Asn446 residue is conserved in mammals but not in more distantly related organisms however computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; 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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