Submissions for variant NM_007194.4(CHEK2):c.15G>A (p.Ser5=)

gnomAD frequency: 0.00004  dbSNP: rs145183886

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000204321	SCV000260320	likely benign	Familial cancer of breast	2024-02-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000214040	SCV000277654	likely benign	Hereditary cancer-predisposing syndrome	2015-08-06	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.
Illumina Laboratory Services, Illumina	RCV000314342	SCV000437731	uncertain significance	CHEK2-Related Cancer Susceptibility	2018-01-13	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	RCV000204321	SCV000488464	likely benign	Familial cancer of breast	2016-04-06	criteria provided, single submitter	clinical testing
GeneDx	RCV001705173	SCV000518108	likely benign	not provided	2018-05-10	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000214040	SCV000684615	likely benign	Hereditary cancer-predisposing syndrome	2016-07-11	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000438041	SCV000917242	likely benign	not specified	2018-10-23	criteria provided, single submitter	clinical testing	Variant summary: CHEK2 c.15G>A alters a non-conserved nucleotide resulting in a synonymous change. 4/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00013 in 240078 control chromosomes, predominantly within the South Asian subpopulation at a frequency of 0.00046 in the gnomAD database. The observed variant frequency within South Asian control individuals is approximately 1.5-fold above the estimated maximal expected allele frequency for a pathogenic variant in CHEK2 causing Hereditary Breast and Ovarian Cancer phenotype (0.00031), suggesting that the variant is a benign polymorphism found primarily in populations of South Asian origin. To our knowledge, no occurrence of c.15G>A in individuals affected with Hereditary Breast and Ovarian Cancer and no experimental evidence demonstrating its impact on protein function have been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and most classified the variant as likely benign. Based on the evidence outlined above, the variant was classified as likely benign.
Sema4, Sema4	RCV000214040	SCV002537402	likely benign	Hereditary cancer-predisposing syndrome	2021-11-15	criteria provided, single submitter	curation
Myriad Genetics, Inc.	RCV000204321	SCV004020097	benign	Familial cancer of breast	2023-03-08	criteria provided, single submitter	clinical testing	This variant is considered benign. This variant is a silent/synonymous amino acid change and it is not expected to impact splicing.
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000214040	SCV004228155	likely benign	Hereditary cancer-predisposing syndrome	2023-10-10	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003491954	SCV004240451	likely benign	Breast and/or ovarian cancer	2023-01-06	criteria provided, single submitter	clinical testing