Submissions for variant NM_007194.4(CHEK2):c.1423T>A (p.Phe475Ile)

gnomAD frequency: 0.00004  dbSNP: rs370968992

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000129382	SCV000184148	uncertain significance	Hereditary cancer-predisposing syndrome	2022-05-24	criteria provided, single submitter	clinical testing	The p.F475I variant (also known as c.1423T>A), located in coding exon 12 of the CHEK2 gene, results from a T to A substitution at nucleotide position 1423. The phenylalanine at codon 475 is replaced by isoleucine, an amino acid with highly similar properties. This alteration behaved as 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 poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
GeneDx	RCV000212464	SCV000210991	uncertain significance	not provided	2023-07-05	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Published functional studies demonstrate no damaging effect: in vivo growth rates similar to wild-type in yeast-based assays (Delimitsou et al., 2019); This variant is associated with the following publications: (PMID: 27997549, 22419737, 19782031, 27616075, 35264596, 30851065)
Invitae	RCV000206734	SCV000262129	uncertain significance	Familial cancer of breast	2024-02-01	criteria provided, single submitter	clinical testing	This sequence change replaces phenylalanine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 475 of the CHEK2 protein (p.Phe475Ile). This variant is present in population databases (rs370968992, gnomAD 0.007%). This missense change has been observed in individual(s) with breast cancer (PMID: 27616075, 35264596). ClinVar contains an entry for this variant (Variation ID: 141046). 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 tolerated. Experimental studies have shown that this missense change does not substantially affect CHEK2 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.
Color Diagnostics, LLC DBA Color Health	RCV000129382	SCV000684592	uncertain significance	Hereditary cancer-predisposing syndrome	2023-05-23	criteria provided, single submitter	clinical testing	This missense variant replaces phenylalanine with isoleucine at codon 475 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 has shown the mutant protein to be functional in a DNA damage repair assay in yeast (PMID: 30851065). This variant has been reported in an individual affected with breast cancer (PMID: 27616075), as well as in an unaffected female over age 70 (https://whi.color.com/variant/22-29090058-A-T). This variant has been identified in 8/265196 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.
Counsyl	RCV000206734	SCV000784837	uncertain significance	Familial cancer of breast	2017-01-13	criteria provided, single submitter	clinical testing
Mendelics	RCV000206734	SCV000839456	uncertain significance	Familial cancer of breast	2018-07-02	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000212464	SCV000888107	uncertain significance	not provided	2023-01-31	criteria provided, single submitter	clinical testing	In the published literature, this variant has been reported in individuals with breast cancer (PMID: 27616075 (2016), 35264596 (2022)), and shown to have a benign effect on DNA damage repair in yeast (PMID: 30851065 (2019)). The frequency of this variant in the general population, 0.000064 (8/124198 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000781308	SCV000919229	uncertain significance	not specified	2018-10-09	criteria provided, single submitter	clinical testing	Variant summary: CHEK2 c.1423T>A (p.Phe475Ile) results in a non-conservative amino acid change located in the Protein kinase domain of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 3.1e-05 in 260162 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1423T>A has been reported in the literature in one individual affected with Breast and Ovarian Cancer. This report does not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and all classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
CeGaT Center for Human Genetics Tuebingen	RCV000212464	SCV001501835	likely benign	not provided	2023-12-01	criteria provided, single submitter	clinical testing	CHEK2: BP4, BS3:Supporting
Sema4, Sema4	RCV000129382	SCV002537372	uncertain significance	Hereditary cancer-predisposing syndrome	2021-12-18	criteria provided, single submitter	curation
Fulgent Genetics, Fulgent Genetics	RCV002483259	SCV002788910	uncertain significance	Familial cancer of breast; Li-Fraumeni syndrome 2; Bone osteosarcoma; Malignant tumor of prostate; Colorectal cancer	2022-03-28	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000206734	SCV004020184	likely benign	Familial cancer of breast	2023-09-05	criteria provided, single submitter	clinical testing	This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752].
PreventionGenetics, part of Exact Sciences	RCV004528850	SCV004105411	uncertain significance	CHEK2-related disorder	2023-07-20	criteria provided, single submitter	clinical testing	The CHEK2 c.1423T>A variant is predicted to result in the amino acid substitution p.Phe475Ile. This variant has been reported in an individual with breast cancer (Table S4, Kraus et al. 2017. PubMed ID: 27616075). In vivo experimental studies using a yeast-based system suggest this variant is functionally benign (Table S1 and Figure S3, Delimitsou et al. 2019. PubMed ID: 30851065). This variant is reported in 0.0064% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/22-29090058-A-T). It is interpreted as uncertain significance by the vast majority of submitters in ClinVar (https://preview.ncbi.nlm.nih.gov/clinvar/variation/141046/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Baylor Genetics	RCV000206734	SCV004217488	uncertain significance	Familial cancer of breast	2023-10-22	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001356630	SCV001551852	uncertain significance	Malignant tumor of breast		no assertion criteria provided	clinical testing	The CHEK2 p.Phe475Ile variant was not identified in the literature nor was it identified in Cosmic, MutDB, or Zhejiang Colon Cancer Database. The variant was identified in dbSNP (ID: rs370968992) “With Uncertain significance allele”, ClinVar (classified as uncertain significance by Ambry Genetics, GeneDx, and Invitae), Clinvitae and the NHLBI GO Exome Sequencing Project in 1 of 4692 chromosomes (frequency 0.0002). The variant was not identified in the 1000 Genomes Project, genome Aggregation or the Exome Aggregation Consortium (August 8th 2016) control databases. The p.Phe475 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and 1 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.