ClinVar Miner

Submissions for variant NM_007194.4(CHEK2):c.170C>T (p.Ser57Phe) (rs730881695)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000160445 SCV000211006 uncertain significance not provided 2021-04-09 criteria provided, single submitter clinical testing Not observed at a significant frequency in large population cohorts (Lek 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with breast cancer (Schoolmeester 2017); Published functional studies demonstrate no damaging effect: growth similar to wild type after DNA damage (Delimitsou 2019); This variant is associated with the following publications: (PMID: 28709830, 30851065)
Invitae RCV000197274 SCV000254933 uncertain significance Familial cancer of breast 2020-10-25 criteria provided, single submitter clinical testing This sequence change replaces serine with phenylalanine at codon 57 of the CHEK2 protein (p.Ser57Phe). The serine residue is highly conserved and there is a large physicochemical difference between serine and phenylalanine. This variant is present in population databases (rs730881695, ExAC 0.001%). This variant has been observed in an individual affected with breast cancer (PMID: 28709830). ClinVar contains an entry for this variant (Variation ID: 182445). Experimental studies have shown that this variant does not substantially affect CHEK2 protein function (PMID: 30851065). 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.
Ambry Genetics RCV000219585 SCV000274859 uncertain significance Hereditary cancer-predisposing syndrome 2019-09-13 criteria provided, single submitter clinical testing The p.S57F variant (also known as c.170C>T), located in coding exon 1 of the CHEK2 gene, results from a C to T substitution at nucleotide position 170. The serine at codon 57 is replaced by phenylalanine, an amino acid with highly dissimilar properties. This variant was detected in conjunction with a pathogenic RAD51C​ mutation in an individual with early-onset breast cancer (Schoolmeester JK et al. Hum. Pathol., 2017 12;70:14-26). 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.
Fulgent Genetics,Fulgent Genetics RCV000515427 SCV000611455 uncertain significance Familial cancer of breast; Li-Fraumeni syndrome 2; Bone osteosarcoma; Malignant tumor of prostate 2017-05-23 criteria provided, single submitter clinical testing
Counsyl RCV000197274 SCV000785625 uncertain significance Familial cancer of breast 2017-10-16 criteria provided, single submitter clinical testing
Color Health, Inc RCV000219585 SCV000913607 uncertain significance Hereditary cancer-predisposing syndrome 2020-12-14 criteria provided, single submitter clinical testing This missense variant replaces serine with phenylalanine at codon 57 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). A functional study in yeast has shown this variant to be benign (PMID: 30851065). This variant has been reported in an individual affected with breast cancer, who also carried a pathogenic RAD51C variant (PMID: 28709830). This variant has been identified in 1/251454 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001193687 SCV001362699 uncertain significance not specified 2019-04-25 criteria provided, single submitter clinical testing Variant summary: CHEK2 c.170C>T (p.Ser57Phe) results in a non-conservative amino acid change in the encoded protein sequence. Five 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-06 in 251454 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. The variant, c.170C>T has been reported in the literature in an individual affected with breast cancer. This patient also carried a RAD51C exon 6 deletion (Schoolmeester_2017). This report however, does not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. In a yeast functional assay, this variant was found to be benign (Delimitsou_2019). However, this evidence does not allow convincing conclusions about the variant effect. Five ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cites the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS - possibly benign.

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