Submissions for variant NM_007194.4(CHEK2):c.1382A>G (p.Asp461Gly)

dbSNP: rs1555913188

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000569874	SCV000665305	uncertain significance	Hereditary cancer-predisposing syndrome	2021-06-18	criteria provided, single submitter	clinical testing	The p.D461G variant (also known as c.1382A>G), located in coding exon 12 of the CHEK2 gene, results from an A to G substitution at nucleotide position 1382. The aspartic acid at codon 461 is replaced by glycine, an amino acid with similar properties. This amino acid position is well 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.
Color Diagnostics, LLC DBA Color Health	RCV000569874	SCV000684585	uncertain significance	Hereditary cancer-predisposing syndrome	2023-04-17	criteria provided, single submitter	clinical testing	This missense variant replaces aspartic acid with glycine at codon 461 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). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with breast cancer (PMID: 29522266). This variant has not been identified 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.
Invitae	RCV000635657	SCV000757078	uncertain significance	Familial cancer of breast	2022-07-02	criteria provided, single submitter	clinical testing	This sequence change replaces aspartic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 461 of the CHEK2 protein (p.Asp461Gly). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with CHEK2-related conditions. ClinVar contains an entry for this variant (Variation ID: 481132). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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.
Mendelics	RCV000635657	SCV000839458	uncertain significance	Familial cancer of breast	2018-07-02	criteria provided, single submitter	clinical testing
Division of Medical Genetics, University of Washington	RCV000635657	SCV001424791	uncertain significance	Familial cancer of breast	2019-09-10	criteria provided, single submitter	clinical testing	To our knowledge, this sequence variant has not been previously reported in the literature. This variant is not present in population databases (https://gnomad.broadinstitute.org/). In silico analyses indicate this is an evolutionarily conserved residue. Thus, it is unknown at this time whether this variant increases cancer risk.