Submissions for variant NM_007194.4(CHEK2):c.755G>A (p.Ser252Asn)

gnomAD frequency: 0.00002  dbSNP: rs587781379

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000129204	SCV000183949	likely benign	Hereditary cancer-predisposing syndrome	2022-10-04	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
GeneDx	RCV000214585	SCV000279244	uncertain significance	not provided	2023-10-05	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with breast, pancreatic, esophageal, and other cancers, but also in healthy controls (Momozawa et al., 2018; Ohmoto et al., 2018; Deng et al., 2019; Chen et al., 2020; Dorling et al., 2021; Wagener et al., 2022); This variant is associated with the following publications: (PMID: 30826992, 36468172, 19782031, 22419737, 30833958, 30287823, 26928463, 27997549, 34570441, 36243179, 32091409, 33471991, 32566746, 31867841, 29667044, 37377590)
Invitae	RCV000227256	SCV000289704	likely benign	Familial cancer of breast	2023-12-02	criteria provided, single submitter	clinical testing
Counsyl	RCV000227256	SCV000488892	uncertain significance	Familial cancer of breast	2016-07-13	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000765620	SCV000896945	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
Color Diagnostics, LLC DBA Color Health	RCV000129204	SCV000903078	likely benign	Hereditary cancer-predisposing syndrome	2016-06-28	criteria provided, single submitter	clinical testing
Cancer Genomics Group, Japanese Foundation For Cancer Research	RCV001030685	SCV001193561	uncertain significance	Hereditary breast ovarian cancer syndrome	2019-05-01	criteria provided, single submitter	research
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001201286	SCV001372405	likely benign	not specified	2020-06-30	criteria provided, single submitter	clinical testing	Variant summary: CHEK2 c.755G>A (p.Ser252Asn) results in a conservative amino acid change in 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 0.00016 in 298804 control chromosomes, predominantly at a frequency of 0.00087 within the East Asian subpopulation in the gnomAD database. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 3 fold of the estimated maximal expected allele frequency for a pathogenic variant in CHEK2 causing Hereditary Breast And Ovarian Cancer Syndrome phenotype (0.00031), strongly suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. c.755G>A has been reported in the literature in individuals affected with pancreatic cancer, breast cancer, or Esophageal squamous cell carcinoma (Ohmoto_2018, Momozawa_2018, Deng_2019, Chen_2019). A large case-control study in Japanese patients with breast cancer showed that odds ratio of this variant is 1.4 (95%CI=0.6-3.1), suggesting that this variant is unlikely to associate with the disease. Co-occurrence with a pathogenic variant has been reported (TP53 c.743G>A , p.Arg248Gln), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (likely benign n=1, VUS n=6). Based on the evidence outlined above, the variant was classified as likely benign.
CeGaT Center for Human Genetics Tuebingen	RCV000214585	SCV001501839	uncertain significance	not provided	2020-11-01	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000129204	SCV002537638	uncertain significance	Hereditary cancer-predisposing syndrome	2021-08-11	criteria provided, single submitter	curation
Myriad Genetics, Inc.	RCV000227256	SCV004020218	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.