Submissions for variant NM_007194.4(CHEK2):c.911T>C (p.Met304Thr)

gnomAD frequency: 0.00001  dbSNP: rs587782033

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000130483	SCV000185352	uncertain significance	Hereditary cancer-predisposing syndrome	2023-04-26	criteria provided, single submitter	clinical testing	The p.M304T variant (also known as c.911T>C), located in coding exon 8 of the CHEK2 gene, results from a T to C substitution at nucleotide position 911. The methionine at codon 304 is replaced by threonine, an amino acid with similar properties. This alteration has been identified in multiple individuals undergoing genetic testing based on a personal and/or family history of cancer (Le Calvez-Kelm F et al. Breast Cancer Res, 2011 Jan;13:R6; Young EL et al. J Med Genet, 2016 06;53:366-76; Isaacsson Velho P et al. Prostate, 2018 04;78:401-407; Liccardo R et al. Int J Mol Med, 2022 Jun;49:; Paduano F et al. Genes (Basel), 2022 Jul;13:). 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.
GeneDx	RCV000590254	SCV000210976	uncertain significance	not provided	2023-06-21	criteria provided, single submitter	clinical testing	Observed in individuals with breast, prostate, or colon cancer (Le Calvez-Kelm et al., 2011; Isaacsson Velho et al., 2018; Paduano et al., 2022; Liccardo R et a., 20220); Published functional studies demonstrate reduced response to DNA damage in a yeast-based assay (Delimitsou et al., 2019); 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: 29368341, 21244692, 26787654, 22419737, 19782031, 30344923, 35886069, 30851065, 31159747, 35475445, 30262796)
Invitae	RCV000534707	SCV000633233	uncertain significance	Familial cancer of breast	2023-09-25	criteria provided, single submitter	clinical testing	This sequence change replaces methionine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 304 of the CHEK2 protein (p.Met304Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast cancer, prostate cancer or Wilms tumor (PMID: 21244692, 29368341, 30344923). ClinVar contains an entry for this variant (Variation ID: 141817). 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). 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	RCV000130483	SCV000684697	uncertain significance	Hereditary cancer-predisposing syndrome	2023-05-30	criteria provided, single submitter	clinical testing	This missense variant replaces methionine with threonine at codon 304 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 that this variant is damaging to CHEK2 function in a yeast-based DNA damage repair assay (PMID: 30851065). This variant has been reported in individuals affected with breast cancer (PMID: 21244692, 26787654, 33471991; Leiden Open Variation Database DB-ID CHEK2_000404, 35886069), prostate cancer (PMID: 29368341), colorectal cancer (PMID: 35475445) and Wilms tumor (PMID: 30344923). This variant has been identified in 1/250794 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	RCV000590254	SCV000698823	uncertain significance	not provided	2017-04-13	criteria provided, single submitter	clinical testing	Variant summary: The CHEK2 c.911T>C (p.Met304Thr) variant involves the alteration of a conserved nucleotide that is 2 basepairs away from an exon-intron junction, resulting in a missense substitution. The variant lies within the Protein kinase domain (InterPro) and 4/4 in silico tools predict a damaging outcome for this variant (SNPs&GO not captured due to low reliability index). 5/5 splice prediction tools predict no significant impact on normal splicing, though ESE finder predicts that this variant may introduce several ESE sites at the locus. However, these predictions have yet to be confirmed by functional studies. This variant is absent from the large control database ExAC and control cohorts included in publications (0/123556 control chromosomes). In the literature, the variant was detected in a female diagnosed with early onset breast cancer, although the lack of cosegregation and co-occurrence data prevents a reliable genotype-phenotype inference (Le Calvez-Kelm_BCR_2011). In addition, multiple clinical diagnostic laboratories/reputable databases have classified this variant as being of uncertain significance. Taken together, this variant is classified as VUS until additional information becomes available.
Genetic Services Laboratory, University of Chicago	RCV001818313	SCV002064732	uncertain significance	not specified	2020-08-27	criteria provided, single submitter	clinical testing	DNA sequence analysis of the CHEK2 gene demonstrated a sequence change, c.911T>C, in exon 9 that results in an amino acid change, p.Met304Thr. This sequence change has been reported in several individuals with prostate cancer, breast cancer and Wilms tumor (PMIDs: 29368341, 21244692, 30344923). This sequence change has also been described in the gnomAD database with a low population frequency of 0.0004% (dbSNP rs587782033). The p.Met304Thr change affects a moderately conserved amino acid residue located in the kinase domain of the CHEK2 protein. The p.Met304Thr substitution appears to be deleterious using three of these four in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). One functional study in yeast shows p.Met304Thr is a damaging variant (PMID: 30851065). Collectively, the clinical significance of the p.Met304Thr change remains unknown at this time.
PreventionGenetics, part of Exact Sciences	RCV003415951	SCV004115467	uncertain significance	CHEK2-related condition	2023-06-23	criteria provided, single submitter	clinical testing	The CHEK2 c.911T>C variant is predicted to result in the amino acid substitution p.Met304Thr. This variant has been reported in individuals with breast cancer, prostate cancer, and Wilms tumor (Le Calvez-Kelm et al. 2011. PubMed ID: 21244692; Isaacsson Velho et al. 2018. PubMed ID: 29368341; Ciceri et al. 2018. PubMed ID: 30344923). Functional studies in yeast showed that this variant is damaging (Delimitsou et al. 2019. PubMed ID: 30851065). This variant is reported in 0.00088% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/22-29095923-A-G), and is interpreted as variant of uncertain significance in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/141817/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.