ClinVar Miner

Submissions for variant NM_007194.4(CHEK2):c.1141A>G (p.Met381Val) (rs375130261)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000129242 SCV000184000 uncertain significance Hereditary cancer-predisposing syndrome 2020-10-02 criteria provided, single submitter clinical testing The p.M381V variant (also known as c.1141A>G), located in coding exon 10 of the CHEK2 gene, results from an A to G substitution at nucleotide position 1141. The methionine at codon 381 is replaced by valine, an amino acid with highly similar properties. This alteration has been detected in a cohort of 1231 colorectal cancer cases (DeRycke MS et al. Mol Genet Genomic Med. 2017 Sep;5:553-569) and in a woman with breast cancer undergoing multi-gene panel testing (Tung N et al. Cancer, 2015 Jan;121:25-33). This alteration behaved as functional in an in vivo, yeast-based growth rate assay (Delimitsou A et al. Hum. Mutat., 2019 05;40:631-648). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
GeneDx RCV000212452 SCV000210984 uncertain significance not provided 2018-03-16 criteria provided, single submitter clinical testing This variant is denoted CHEK2 c.1141A>G at the cDNA level, p.Met381Val (M381V) at the protein level, and results in the change of a Methionine to a Valine (ATG>GTG). This variant has been observed in at least one individual with early-onset colorectal cancer (DeRycke 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 within the protein kinase domain (Cai 2009, Roeb 2012). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether CHEK2 Met381Val is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000227000 SCV000289647 uncertain significance Familial cancer of breast 2020-10-27 criteria provided, single submitter clinical testing This sequence change replaces methionine with valine at codon 381 of the CHEK2 protein (p.Met381Val). The methionine residue is highly conserved and there is a small physicochemical difference between methionine and valine. This variant is present in population databases (rs375130261, ExAC 0.005%). This variant has been observed in individual(s) with breast cancer and colorectal cancer (PMID: 25186627, 28944238). ClinVar contains an entry for this variant (Variation ID: 140959). 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: Possibly Damaging; Align-GVGD: Class C0). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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.
Counsyl RCV000227000 SCV000488278 uncertain significance Familial cancer of breast 2016-02-16 criteria provided, single submitter clinical testing
Color Health, Inc RCV000129242 SCV000537598 uncertain significance Hereditary cancer-predisposing syndrome 2020-08-18 criteria provided, single submitter clinical testing This missense variant replaces methionine with valine at codon 381 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. An experimental functional study showed no impact of this variant in a yeast DNA damage repair assay (PMID: 30851065). This variant has been reported in individuals affected with breast and colorectal cancer in the literature (PMID: 25186627, 28944238). This variant has been identified in 10/282330 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.
Mendelics RCV000227000 SCV000839465 uncertain significance Familial cancer of breast 2018-07-02 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000212452 SCV000888097 uncertain significance not provided 2018-07-12 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000764375 SCV000895410 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
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000781303 SCV000919223 uncertain significance not specified 2018-08-13 criteria provided, single submitter clinical testing Variant summary: CHEK2 c.1141A>G (p.Met381Val) results in a conservative amino acid change located in the Protein kinase domain of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-05 in 276850 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in CHEK2 causing Hereditary Breast and Ovarian Cancer (4e-05 vs 0.00031), allowing no conclusion about variant significance. c.1141A>G has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer (Tung_2014). This report does not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001354869 SCV001549585 uncertain significance Malignant tumor of breast no assertion criteria provided clinical testing The CHEK2 p.Met381Val variant was not identified in the literature nor was it identified in the MutDB, Zhejiang Colon Cancer Database, databases. The variant was identified in the following databases: dbSNP (ID: rs375130261) as With Uncertain significance allele, ClinVar (classified as uncertain significance by Ambry Genetics, GeneDx, Invitae, Counsyl, Color Genomics), Clinvitae, and Cosmic. The variant was identified in control databases in 11 of 276850 chromosomes at a frequency of 0.00004 (Genome Aggregation Database Feb 27, 2017). It was observed in the following populations: Latino in 1 of 34410 chromosomes (freq: 0.00003), European in 10 of 126376 chromosomes (freq: 0.0001); it was not observed in the African, Other, Ashkenazi Jewish, East Asian, Finnish, and South Asian populations. The p.Met381 residue is conserved across mammals and other organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and 3 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing. However, this information is not predictive enough to assume pathogenicity. 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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