rs77130927
Variant summary
Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_Strong
The NM_001257387.2(CHEK2):c.-240C>T variant causes a 5 prime UTR premature start codon gain change. The variant allele was found at a frequency of 0.000828 in 1,613,844 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_001257387.2 5_prime_UTR_premature_start_codon_gain
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -4 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.000619 AC: 94AN: 151932Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00100 AC: 252AN: 251406Hom.: 0 AF XY: 0.00102 AC XY: 139AN XY: 135896
GnomAD4 exome AF: 0.000850 AC: 1243AN: 1461790Hom.: 0 Cov.: 32 AF XY: 0.000854 AC XY: 621AN XY: 727196
GnomAD4 genome AF: 0.000618 AC: 94AN: 152054Hom.: 0 Cov.: 32 AF XY: 0.000686 AC XY: 51AN XY: 74310
ClinVar
Submissions by phenotype
not provided Uncertain:4Benign:4
Variant summary: The CHEK2 c.538C>T (p.Arg180Cys) variant involves the alteration of a conserved nucleotide. 3/4 in silico tools predict a damaging outcome for this variant (SNPs&GO not captured due to low reliability index). This variant was found in 168/123378 control chromosomes, predominantly observed in the East Asian subpopulation at a frequency of 0.0040472 (35/8648). This frequency is about 142 times the estimated maximal expected allele frequency of a pathogenic CHEK2 variant (0.0000284), suggesting this is likely a benign polymorphism found primarily in the populations of East Asian origin. The variant has been reported in numerous affected individuals in the literature including breast and prostate cancer patients, however no co-segregation and limited co-occurrence data is provided by these studies. In addition, the variant is also reported in unaffected controls in these studies, suggesting the variant is not causitive in these populations. In a yeast-based functional assay, the variant had an intermediate response to DNA damage (Roeb_2012). Multiple clinical diagnostic laboratories/reputable databases classified this variant as a VUS while one has classified it as likely benign. Taken together, this variant is classified as likely benign. -
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The CHEK2 p.Arg180Cys variant was identified in 172 of 93852 proband chromosomes (frequency: 0.002) from individuals or families with hereditary breast and ovarian cancer, prostate cancer and Lynch syndrome and was present in 147 of 89446 control chromosomes (frequency: 0.002) from healthy individuals (Dong 2003, Dufault 2004, Kleibl 2008, Laitman 2007, Mohamad 2015, Mohelnikova Duchonova 2010, Ng 2016, Southey 2016, Yurgelun 2015). The variant was also identified in dbSNP (ID: rs77130927) as “With other allele”, ClinVar (classified as benign by Color Genomics, Ambry Genetics, and Mendelics Analise Genomica; as likely benign by Invitae and Integrated Genetics; and as uncertain significance by GeneDx, Counsyl, and 4 other submitters). The variant was identified in control databases in 261 of 277166 chromosomes at a frequency of 0.0009, increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 14 of 24018 chromosomes (freq: 0.0006), Other in 6 of 6468 chromosomes (freq: 0.0009), Latino in 2 of 34420 chromosomes (freq: 0.00006), European (Non-Finnish) in 153 of 126674 chromosomes (freq: 0.001), Ashkenazi Jewish in 2 of 10152 chromosomes (freq: 0.0002), East Asian in 58 of 18866 chromosomes (freq: 0.003), European (Finnish) in 5 of 25788 chromosomes (freq: 0.0002), and South Asian in 21 of 30780 chromosomes (freq: 0.0007). In a functional yeast assay, the response of the p.Arg180Cys CHEK2 variant to DNA damage was found to be decreased to 0.64 of wild type (1.00; Roeb 2012). A large study of the Breast Cancer Association Consortium found an association with breast cancer risk to be 1.33 odds ratio (Southey 2016). The p.Arg180 residue is conserved in 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) 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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In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Case-control studies are inconclusive regarding association with breast cancer (Southy 2016, Decker 2017); Observed in individuals with breast, prostate, or ovarian cancer (Dong 2003, Dufault 2004, Kleibl 2008, Mohelnikova-Duchonova 2010, Le Calvez-Kelm 2011, Liu 2011, Mohamad 2015, Ng 2016, Chirasophon 2017, Xie 2017); Also known as CHEK2 c.667C>T (p.Arg223Cys); Published functional studies are inconclusive: intermediate response to DNA damage (Walsh 2011, Roeb 2012); This variant is associated with the following publications: (PMID: 26757417, 26483394, 28580595, 18085035, 30826992, 31060593, 25629968, 12533788, 22995991, 25980754, 25525159, 15095295, 20643596, 21618645, 24549055, 21244692, 27153395, 27498913, 22419737, 27595995, 21744992, 18058223, 18996005, 27621404, 23960188, 27783279, 22006311, 23555315, 28188963, 28452373, 28779002, 19782031, 29879026, 29470806, 30287823, 30851065, 31050813, 31422574, 29667044, 29263802, 32566746, 32041497, 33326660, 32906215) -
BS3_supporting -
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Familial cancer of breast Uncertain:3Benign:3
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This variant was classified as: Uncertain significance. The available evidence on this variant's pathogenicity is insufficient or conflicting. The following ACMG criteria were applied in classifying this variant: PP3,BP6. -
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This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752]. -
Hereditary cancer-predisposing syndrome Uncertain:1Benign:3
This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
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Hereditary breast ovarian cancer syndrome Uncertain:2Benign:1
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not specified Uncertain:2
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Breast and/or ovarian cancer Uncertain:1
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CHEK2-related cancer predisposition Uncertain:1
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). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
Malignant tumor of prostate Uncertain:1
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CHEK2-related disorder Benign:1
This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at