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 2018-11-03 criteria provided, single submitter clinical testing This variant is denoted CHEK2 c.170C>T at the cDNA level, p.Ser57Phe (S57F) at the protein level, and results in the change of a Serine to a Phenylalanine (TCT>TTT). This variant has been reported in an individual with a personal and family history of breast cancer who was also found to harbor a large RAD51C deletion (Schoolmeester 2017). CHEK2 Ser57Phe was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in SQ/TQ domain (Bartek 2001, Desrichard 2011). In silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Based on currently available evidence, it is unclear whether CHEK2 Ser57Phe is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000197274 SCV000254933 uncertain significance Familial cancer of breast 2019-12-05 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). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). 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 Insufficient or conflicting evidence
Fulgent Genetics,Fulgent Genetics RCV000515427 SCV000611455 uncertain significance Familial cancer of breast; Li-Fraumeni syndrome 2; 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 RCV000219585 SCV000913607 uncertain significance Hereditary cancer-predisposing syndrome 2020-03-16 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America 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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