Submissions for variant NM_007194.4(CHEK2):c.962A>C (p.Glu321Ala)

gnomAD frequency: 0.00004  dbSNP: rs374395284

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000217252	SCV000276161	uncertain significance	Hereditary cancer-predisposing syndrome	2023-09-20	criteria provided, single submitter	clinical testing	The p.E321A variant (also known as c.962A>C), located in coding exon 8 of the CHEK2 gene, results from an A to C substitution at nucleotide position 962. The glutamic acid at codon 321 is replaced by alanine, an amino acid with dissimilar properties. This alteration was detected in a cohort of 1663 Brazilian breast cancer patients who underwent hereditary multigene panel testing (Guindalini RSC et al. Sci Rep, 2022 Mar;12:4190). This alteration was also 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;29:3037-3050). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae	RCV000228310	SCV000289719	uncertain significance	Familial cancer of breast	2024-01-08	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with alanine, which is neutral and non-polar, at codon 321 of the CHEK2 protein (p.Glu321Ala). This variant is present in population databases (rs374395284, gnomAD 0.01%). This missense change has been observed in individual(s) with breast cancer (PMID: 35264596). ClinVar contains an entry for this variant (Variation ID: 232111). 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.
GeneDx	RCV000522320	SCV000618399	uncertain significance	not provided	2022-12-22	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; Also known as c.1091A>C p.(E364A); This variant is associated with the following publications: (PMID: 31398194, 19782031, 22419737)
Color Diagnostics, LLC DBA Color Health	RCV000217252	SCV000689751	uncertain significance	Hereditary cancer-predisposing syndrome	2020-01-07	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with alanine at codon 321 of the CHEK2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 5/251484 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	RCV000228310	SCV000839472	uncertain significance	Familial cancer of breast	2018-07-02	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000522320	SCV001134176	uncertain significance	not provided	2019-06-20	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000522320	SCV002064091	uncertain significance	not provided	2021-11-01	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002478800	SCV002793555	uncertain significance	Familial cancer of breast; Li-Fraumeni syndrome 2; Bone osteosarcoma; Malignant tumor of prostate; Colorectal cancer	2021-11-10	criteria provided, single submitter	clinical testing
Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	RCV003137823	SCV003806766	uncertain significance	Li-Fraumeni syndrome 2	2022-03-26	criteria provided, single submitter	clinical testing	ACMG classification criteria: PM2 moderated