rs145754558
Variant summary
Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2
The NM_007194.4(CHEK2):c.593-14C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0015 in 1,457,612 control chromosomes in the GnomAD database, including 24 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).
Frequency
Consequence
NM_007194.4 intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -20 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00237 AC: 360AN: 152152Hom.: 3 Cov.: 32
GnomAD3 exomes AF: 0.00312 AC: 612AN: 195858Hom.: 8 AF XY: 0.00294 AC XY: 310AN XY: 105400
GnomAD4 exome AF: 0.00140 AC: 1825AN: 1305342Hom.: 21 Cov.: 20 AF XY: 0.00137 AC XY: 893AN XY: 653132
GnomAD4 genome AF: 0.00236 AC: 359AN: 152270Hom.: 3 Cov.: 32 AF XY: 0.00345 AC XY: 257AN XY: 74460
ClinVar
Submissions by phenotype
not specified Benign:5
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This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
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Familial cancer of breast Benign:3
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This variant is considered 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]. -
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Hereditary cancer-predisposing syndrome Benign:3
This alteration is classified as likely 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. -
BS1, BP4 c.593-14C>T is an intronic variant located close to a canonical splice site. The variant allele was found in 130/16644 alleles, with a filter allele frequency of 0.63% at 99% confidence in the gnomAD v2.1.1 database (East Asian)(BS1). The SpliceAI algorithm predicts no significant impact on splicing (BP4). To our knowledge, neither clinical data nor functional studies have been reported for this variant It has been identified in the following databases, ClinVar (10x benign, 3x likely benign) and LOVD (4x benign). Based on currently available information, the variant c.593-14C>T is classified as a likely benign variant according to ACMG guidelines. -
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CHEK2-related cancer predisposition Benign:1
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
not provided Benign:1
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Malignant tumor of breast Benign:1
The CHEK2 c.593-14C>T variant was not identified in the literature nor was it identified in the Zhejiang Colon Cancer Database, databases. The variant was identified in dbSNP (ID: rs145754558) as “With Likely benign allele”, ClinVar (as benign by GeneDx, Counsyl), Clinvitae (as benign by ClinVar), databases. The variant was identified in control databases in 752 of 221734 (8 homozygous) chromosomes at a frequency of 0.003 in the following populations: other in 22 of 5482 chromosomes (freq. 0.004), Latino in 1 of 28996 chromosomes (freq. 0.000034), European in 114 of 93630 (1 homozygous) chromosomes (freq. 0.0012), Ashkenazi Jewish in 22 of 9042 chromosomes (freq. 0.0024), East Asian in 128 of 16184 (1 homozygous) chromosomes (freq. 0.008), Finnish in 460 of 22300 (6 homozygous) chromosomes (freq. 0.02),and South Asian in 5 of 25738 chromosomes (freq. 0.0002), increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Consortium Feb 27, 2017). 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 although we would lean towards a more benign role for this variant. This variant is classified as likely benign. -
Hereditary breast ovarian cancer syndrome Benign:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at