Submissions for variant NM_007194.4(CHEK2):c.1590C>T (p.Ala530=)

gnomAD frequency: 0.00001  dbSNP: rs786201796

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000164268	SCV000214893	likely benign	Hereditary cancer-predisposing syndrome	2015-01-21	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000228877	SCV000289673	likely benign	Familial cancer of breast	2023-12-27	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000164268	SCV000684613	likely benign	Hereditary cancer-predisposing syndrome	2015-10-30	criteria provided, single submitter	clinical testing
GeneDx	RCV001284480	SCV000714640	likely benign	not provided	2019-12-05	criteria provided, single submitter	clinical testing
Counsyl	RCV000228877	SCV000786067	likely benign	Familial cancer of breast	2018-02-15	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001284480	SCV001470307	likely benign	not provided	2020-01-21	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000228877	SCV004020104	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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004700506	SCV005203465	likely benign	not specified	2024-07-18	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001357970	SCV001553585	likely benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The CHEK2 p.Ala530= variant was not identified in the literature nor was it identified in Cosmic or Zhejiang University Database. The variant was identified in dbSNP (ID: rs786201796 as "With Likely benign, Uncertain significance allele") and ClinVar (classified as likely benign by Ambry Genetics, Invitae, Color Genomics, GeneDx, and Counsyl). The variant was identified in control databases in 4 of 260074 chromosomes at a frequency of 0.00002 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European in 3 of 121966 chromosomes (freq: 0.00003), and South Asian in 1 of 30508 chromosomes (freq: 0.00003); it was not observed in the African, Other, Latino, Ashkenazi Jewish, East Asian, and Finnish, populations. The p.Ala530= variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. In addition, 4 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.