chr22-28687892-G-A
Variant summary
Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_StrongBP6BS2_Supporting
The NM_007194.4(CHEK2):c.*5C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000107 in 1,594,054 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_007194.4 3_prime_UTR
Scores
Clinical Significance
Conservation
Publications
- CHEK2-related cancer predispositionInheritance: AD Classification: DEFINITIVE Submitted by: Ambry Genetics
- hereditary breast carcinomaInheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen
- Li-Fraumeni syndrome 2Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
- acute myeloid leukemiaInheritance: AD Classification: MODERATE Submitted by: Genomics England PanelApp
- hereditary nonpolyposis colon cancerInheritance: AD Classification: LIMITED Submitted by: ClinGen
- familial ovarian cancerInheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
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ACMG classification
Our verdict: Likely_benign. The variant received -6 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000197 AC: 3AN: 152148Hom.: 0 Cov.: 32 show subpopulations
GnomAD2 exomes AF: 0.00000856 AC: 2AN: 233600 AF XY: 0.00000779 show subpopulations
GnomAD4 exome AF: 0.00000971 AC: 14AN: 1441906Hom.: 0 Cov.: 30 AF XY: 0.00000975 AC XY: 7AN XY: 717814 show subpopulations
GnomAD4 genome AF: 0.0000197 AC: 3AN: 152148Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74316 show subpopulations
ClinVar
Submissions by phenotype
not provided Uncertain:1Benign:1
The CHEK2 c.*5C>T variant was not identified in the literature nor was it identified in the Cosmic, MutDB, and Zhejiang University Database. The variant was identified in dbSNP (ID: rs587781367) as “With Uncertain significance allele”, in ClinVar (classified uncertain significance by Ambry Genetics and likely benign by GeneDx), and in control databases in 2 of 229070 chromosomes at a frequency of 0.000009 (Genome Aggregation Database Feb 27, 2017). It was observed in the following populations: African in 1 of 13844 chromosomes (freq: 0.00007) and South Asian in 1 of 30508 chromosomes (freq: 0.00003); it was not observed in the Other, Latino, European Non-Finnish, Ashkenazi Jewish, East Asian, and European Finnish populations. The variant occurs in the 3’UTR but is not in a region known to affect transcriptional termination. 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. -
See Variant Classification Assertion Criteria. -
Hereditary cancer-predisposing syndrome Uncertain:1
The c.*5C>T variant is located in the 3' untranslated region (3’ UTR) of the CHEK2 gene. This variant results from a C to T substitution 5 nucleotides after the last translated exon of the CHEK2 gene. This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 3663 samples (7326 alleles) with coverage at this position. To date, this alteration has been detected with an allele frequency of approximately 0.002% (greater than 130000 alleles tested) in our clinical cohort. This nucleotide position is poorly conserved in available vertebrate species. Since supporting evidence is limited at this time, the clinical significance of c.*5C>T remains unclear. -
Familial cancer of breast Benign:1
This variant is considered benign. This variant occurs in the non-coding 3' untranslated region of the gene, and is not expected to impact protein function. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at