Submissions for variant NM_007194.4(CHEK2):c.157T>A (p.Ser53Thr)

gnomAD frequency: 0.00002  dbSNP: rs371657037

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000132037	SCV000187096	uncertain significance	Hereditary cancer-predisposing syndrome	2024-02-19	criteria provided, single submitter	clinical testing	The p.S53T variant (also known as c.157T>A), located in coding exon 1 of the CHEK2 gene, results from a T to A substitution at nucleotide position 157. The serine at codon 53 is replaced by threonine, an amino acid with similar properties. This alteration was detected by genome sequencing in an ancestrally diverse cohort of 681 healthy individuals (Bodian DL et al. PLoS One. 2014 Apr 11;9(4):e94554). This alteration was seen in 0/732 breast cancer patients, 0/189 colorectal cancer patients and 1/490 cancer-free elderly controls in a Turkish population (Akcay IM et al. Int J Cancer, 2021 01;148:285-295). In another study, this variant was reported in 5/60,466 breast cancer cases and in 3/53,461 controls (Dorling et al. N Engl J Med 2021 02;384:428-439). This alteration was reported as functional in a study assessing CHEK2-complementation through quantification of KAP1 phosphorylation and CHK2 autophosphorylation in human RPE1-CHEK2-knockout cells (Stolarova L et al. Clin Cancer Res. 2023 Aug;29(16):3037-3050). 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	RCV000766741	SCV000278919	uncertain significance	not provided	2024-04-07	criteria provided, single submitter	clinical testing	Identified in individuals with breast or colorectal cancer, but also present in unaffected controls (PMID: 24728327, 32658311, 33471991); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 31398194, 30344923, 33471991, 24728327, 32658311, 22419737, Ates2022[Article], 35534704, 22114986, 11733767)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000231176	SCV000289671	uncertain significance	Familial cancer of breast	2023-12-26	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with threonine, which is neutral and polar, at codon 53 of the CHEK2 protein (p.Ser53Thr). This variant is present in population databases (rs371657037, gnomAD 0.01%). This missense change has been observed in individual(s) with Wilms tumor (PMID: 30344923). ClinVar contains an entry for this variant (Variation ID: 133888). 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. 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.
Illumina Laboratory Services, Illumina	RCV004556735	SCV000437729	uncertain significance	CHEK2-related cancer predisposition	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Counsyl	RCV000231176	SCV000489481	uncertain significance	Familial cancer of breast	2016-10-11	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000132037	SCV000684610	uncertain significance	Hereditary cancer-predisposing syndrome	2023-04-24	criteria provided, single submitter	clinical testing	This missense variant replaces serine with threonine at codon 53 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). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with ovarian cancer (DOI: 10.26650/experimed.1187969) or breast cancer (PMID: 33471991), but also in control individuals (PMID: 24728327, 32658311, 33471991). This variant has been identified in 12/251418 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.
Mendelics	RCV000231176	SCV000839504	uncertain significance	Familial cancer of breast	2018-07-02	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000765627	SCV000896952	uncertain significance	Familial cancer of breast; Li-Fraumeni syndrome 2; Bone osteosarcoma; Malignant tumor of prostate	2018-10-31	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000120553	SCV002041722	uncertain significance	not specified	2023-12-12	criteria provided, single submitter	clinical testing	Variant summary: CHEK2 c.157T>A (p.Ser53Thr) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.8e-05 in 251418 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in CHEK2 causing Hereditary Breast And Ovarian Cancer Syndrome (4.8e-05 vs 0.00031), allowing no conclusion about variant significance. c.157T>A has been reported in the literature in individuals affected with breast cancer (e.g. Dorling_2021, de Oliveira_2022) and also in unaffected controls (e.g. Bodian_2014, Ackay_2021, Dorling_2021). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. A co-occurrence with a pathogenic variant has been reported in an individual with a personal and family history of breast cancer (BRCA1 c.5074+2T>C; de Oliveira_2022), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 32658311, 24728327, 30344923, 33471991, 35534704). Nine submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Eight submitters have classified the variant as uncertain significance and one classified it as likely benign. Based on the evidence outlined above, the variant was classified as uncertain significance.
Myriad Genetics, Inc.	RCV000231176	SCV004020229	likely benign	Familial cancer of breast	2023-03-09	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].
Baylor Genetics	RCV000231176	SCV004215853	uncertain significance	Familial cancer of breast	2024-02-24	criteria provided, single submitter	clinical testing
ITMI	RCV000120553	SCV000084707	not provided	not specified	2013-09-19	no assertion provided	reference population