ClinVar Miner

Submissions for variant NM_007194.4(CHEK2):c.-4C>T (rs374938148)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000589024 SCV000149886 uncertain significance not provided 2018-11-15 criteria provided, single submitter clinical testing This variant is denoted CHEK2 c.-4C>T and describes a nucleotide substitution four base pairs upstream of the ATG translational start site of the CHEK2 gene. The surrounding sequence, with the base that is substituted in brackets, is AGGT[C/T]GTGA. It lies within the ?consensus? Kozak sequence, the nucleotides which play a major role in the initiation of translation and which lie just upstream of the ATG start codon. CHEK2 c.-4C>T has been observed in women with breast cancer as well as in a woman with ovarian cancer whose tumor showed loss of heterozygosity for the CHEK2 locus and only faint protein expression on immunohistochemistry, suggesting this variant may have been involved in tumorigenesis (Williams 2006, Decker 2017). CHEK2 c.-4C>T was observed at an allele frequency of 0.012%, (13/105,550) in individuals of European ancestry in large population cohorts (Lek 2016). The cytosine (C) nucleotide that is altered is not conserved. While the c.-4C>T variant does not alter or create a new start codon (ATG), it is possible that it may have an effect on the initiation of the translation process. Based on currently available evidence, it is unclear whether CHEK2 c.-4C>T is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000115977 SCV000215929 uncertain significance Hereditary cancer-predisposing syndrome 2017-03-28 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Counsyl RCV000232150 SCV000489336 uncertain significance Familial cancer of breast 2016-09-20 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000589024 SCV000698808 uncertain significance not provided 2016-10-06 criteria provided, single submitter clinical testing Variant summary: The CHEK2 c.-4C>T variant involves the alteration of a non-conserved nucleotide at a position -4 relative to the initiation codon. One in silico tool predicts a benign outcome for this variant, but it lies within the Kozak sequence, a region that plays a role in the initiation of translation. However, in the absence of RNA or functional studies, the actual effect of this variant is unknown. This variant was found in 7/120220 control chromosomes, predominantly observed in the African and European non-Finnish subpopulations at a frequency of 0.0000996 (1/10036) and 0.0000912 (6/65754), respectively. These frequencies are 3-4 times the estimated maximal expected allele frequency of a pathogenic CHEK2 variant (0.0000284), suggesting this variant may be a benign polymorphism. Although it was observed in one woman with ovarian cancer whose tumor showed loss of heterozygosity and only faint protein expression by IHC, both of which suggest this variant may have been involved in tumorigenesis (Williams 2006), there are no other patient reports and no co-segregation data available. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. Taken together, this variant is classified as VUS-possibly benign until additional information is available.
Mendelics RCV000232150 SCV000839508 uncertain significance Familial cancer of breast 2018-07-02 criteria provided, single submitter clinical testing
Color RCV000115977 SCV000902801 likely benign Hereditary cancer-predisposing syndrome 2016-10-26 criteria provided, single submitter clinical testing

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