Submissions for variant NM_007194.4(CHEK2):c.751A>T (p.Ile251Phe)

gnomAD frequency: 0.00009  dbSNP: rs587780189

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000587105	SCV000149939	uncertain significance	not provided	2023-07-10	criteria provided, single submitter	clinical testing	Observed in individuals with a personal or family history of breast, prostate, colorectal, or other cancers, as well as in healthy controls (Dong et al., 2003; Desrichard et al., 2011; Le Calvez-Kelm et al., 2011; Yurgelun et al., 2015; Ballinger et al., 2016; Pearlman et al., 2017; Yurgelun et al., 2017; Hauke et al., 2018; Dorling et al., 2021); Published functional studies demonstrate reduced response to DNA damage in a yeast-based assay and intermediate impact on kinase activity in a mouse ES study (Delimitsou et al., 2019; Boonen et al., 2021); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 31398194, 12533788, 22114986, 25980754, 26787654, 27978560, 21244692, 28135145, 27498913, 29596542, 29522266, 28843361, 30851065, 34903604, 33471991, 35127508, 22419737, 19782031, 35441217)
Ambry Genetics	RCV000116030	SCV000185152	uncertain significance	Hereditary cancer-predisposing syndrome	2021-12-16	criteria provided, single submitter	clinical testing	The p.I251F variant (also known as c.751A>T), located in coding exon 5 of the CHEK2 gene, results from an A to T substitution at nucleotide position 751. The isoleucine at codon 251 is replaced by phenylalanine, an amino acid with highly similar properties. This alteration is located in the CHK2 kinase domain and has been detected in cohorts of individuals with hereditary breast cancer, colorectal cancer younger than 50 years, sarcoma, as well as familial prostate cancer (Desrichard A et al. Breast Cancer Res. 2011;13:R119; Dong X et al. Am. J. Hum. Genet. 2003 Feb;72:270-80; Ballinger ML et al. Lancet Oncol. 2016 Sep;17:1261-71; Pearlman R et al. JAMA Oncol. 2017 Apr;3:464-471). In one case-control study, this alteration was not detected in 1313 breast cancer patients diagnosed at or before age 45, but it was seen in 1/1123 healthy controls (Le Calvez-Kelm F et al. Breast Cancer Res. 2011 Jan;13:R6). In another study, this variant was reported in 3/60,466 breast cancer cases and in 0/53,461 controls (Dorling et al. N Engl J Med. 2021 02;384:428-439). This alteration behaved as non-functional in an in vivo yeast-based growth rate assay (Delimitsou A et al. Hum. Mutat. 2019 05;40:631-648). 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.
Invitae	RCV000206871	SCV000261185	uncertain significance	Familial cancer of breast	2024-01-10	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 251 of the CHEK2 protein (p.Ile251Phe). This variant is present in population databases (rs587780189, gnomAD 0.03%). This missense change has been observed in individual(s) with prostate cancer and breast cancer (PMID: 12533788, 22114986, 25980754, 27978560). ClinVar contains an entry for this variant (Variation ID: 128086). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects CHEK2 function (PMID: 30851065, 34903604). 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000212436	SCV000601179	uncertain significance	not specified	2017-06-03	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000116030	SCV000684685	uncertain significance	Hereditary cancer-predisposing syndrome	2023-01-09	criteria provided, single submitter	clinical testing	This missense variant replaces isoleucine with phenylalanine at codon 251 of the CHEK2 protein. Computational prediction tool suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Functional studies have reported the mutant protein to be non-functional in a yeast complementation assay (PMID: 30851065) and to show impaired kinase activity toward a downstream target protein Kap1 despite intact auto-phosphorylation (PMID: 34903604). This variant has been reported in individuals affected with breast cancer (PMID: 22114986, 29522266; Color internal data), colorectal cancer (PMID: 27978560), suspected Lynch syndrome (PMID: 25980754) and prostate cancer (PMID 12533788). Some of these affected individuals also carried a pathogenic variant in a different gene that could explain the observed phenotype (PMID: 2797856; Color internal data). This variant has also been observed in an unaffected control individual (PMID: 21244692). This variant has been identified in 5/282756 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	RCV000212436	SCV000698818	uncertain significance	not specified	2022-05-02	criteria provided, single submitter	clinical testing	Variant summary: CHEK2 c.751A>T (p.Ile251Phe) results in a non-conservative amino acid change located in the Protein kinase domain (IPR000719) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 255478 control chromosomes (gnomAD, and publication data). c.751A>T has been reported in the literature in individuals undergoing multigene panel testing within settings of breast cancer (e.g. Desrichard_2011, Young_2016, Hauke_2018, Dorling_2021), in a family with prostate cancer where this variant did not segregate with disease among two genotyped affected family members (Dong_2003), and in individuals with colorectal cancers (Yurgelun_2015, Yurgelun_2017, Pearlman_2016). At least one co-occurrence with another pathogenic variant has been reported in a female with MMR proficient colorectal cancer (BRCA2 c.1755_1759del, p.K585Nfs*3, Pearlman_2016), providing supporting evidence for a benign role. These data do not allow clear conclusions about variant significance. At least two functional studies reported experimental evidence evaluating an impact on protein function, and assigned a "damaging" functional classification in a yeast-based functional assay evaluating the DNA repair-ability after chemically induced DNA damage (Delimitsou_2019), while another study reported moderately reduced autophosphorylation, with severely reduced (~15%) kinase activity toward the phosphorylation of target protein KAP1 in a CHEK2 knockout mouse embryonic stem cell system (Boonen_2022). Nine ClinVar submitters have assessed this variant since 2014: all submitters classified the variant as of uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
Counsyl	RCV000206871	SCV000785994	uncertain significance	Familial cancer of breast	2018-01-30	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000587105	SCV000806887	uncertain significance	not provided	2017-09-08	criteria provided, single submitter	clinical testing
Mendelics	RCV000206871	SCV000839480	uncertain significance	Familial cancer of breast	2018-07-02	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000212436	SCV002070510	uncertain significance	not specified	2019-11-12	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000116030	SCV002537636	uncertain significance	Hereditary cancer-predisposing syndrome	2021-12-18	criteria provided, single submitter	curation
Fulgent Genetics, Fulgent Genetics	RCV002490783	SCV002781122	uncertain significance	Familial cancer of breast; Li-Fraumeni syndrome 2; Bone osteosarcoma; Malignant tumor of prostate; Colorectal cancer	2022-04-01	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000206871	SCV004020211	uncertain significance	Familial cancer of breast	2023-03-09	criteria provided, single submitter	clinical testing	This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.
Baylor Genetics	RCV000206871	SCV004217588	uncertain significance	Familial cancer of breast	2023-08-25	criteria provided, single submitter	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000587105	SCV002034938	uncertain significance	not provided		no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000587105	SCV002035553	uncertain significance	not provided		no assertion criteria provided	clinical testing