Submissions for variant NM_007194.4(CHEK2):c.485A>G (p.Asp162Gly)

gnomAD frequency: 0.00001  dbSNP: rs587781652

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000129786	SCV000184595	uncertain significance	Hereditary cancer-predisposing syndrome	2024-02-23	criteria provided, single submitter	clinical testing	The p.D162G variant (also known as c.485A>G), located in coding exon 3 of the CHEK2 gene, results from an A to G substitution at nucleotide position 485. The aspartic acid at codon 162 is replaced by glycine, an amino acid with similar properties. This alteration was reported in a Brazilian cohort of breast cancer patients (Urbina-Jara LK et al. Genes (Basel), 2019 10;10:). This alteration behaved as non-functional in an in vivo, yeast-based growth rate assay (Delimitsou A et al. Hum. Mutat., 2019 05;40:631-648). This alteration was also reported as damaging in an mES cell-based assay of CHEK2 activity (Boonen RACM et al. Cancer Res, 2022 02;82:615-631). This alteration was also reported as functionally impaired in another study using CHEK2-complementation assays quantifying KAP1 phosphorylation and CHK2 autophosphorylation in human RPE1-CHEK2-knockout cells (Stolarova L et al. Clin Cancer Res, 2023 Jul;:OF1-OF14). 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000461401	SCV000550421	pathogenic	Familial cancer of breast	2024-01-09	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 162 of the CHEK2 protein (p.Asp162Gly). This variant is present in population databases (rs587781652, gnomAD 0.0009%). This missense change has been observed in individual(s) with prostate cancer (PMID: 34903604). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 141314). 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. Experimental studies have shown that this missense change affects CHEK2 function (PMID: 30851065, 34903604). Studies have shown that this missense change is associated with inconclusive levels of altered splicing (Invitae). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000480654	SCV000566329	likely pathogenic	not provided	2024-02-09	criteria provided, single submitter	clinical testing	Observed in three brothers with prostate cancer, in a patient with ovarian cancer, and in unaffected controls (PMID: 30535581, 32546565, 34903604); Published functional studies demonstrate a damaging effect: reduced kinase activity in mammalian cell assays and impaired response to DNA damage in a yeast assay (PMID: 30851065, 34903604, 37449874); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 31398194, 31658756, 32546565, 30535581, 34903604, 22419737, 19782031, 37449874, 30851065)
Mendelics	RCV000461401	SCV000839489	uncertain significance	Familial cancer of breast	2018-07-02	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000129786	SCV000906769	uncertain significance	Hereditary cancer-predisposing syndrome	2022-09-12	criteria provided, single submitter	clinical testing	This missense variant replaces aspartic acid with glycine at codon 162 of the CHEK2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have demonstrated this variant to disrupt CHEK2 protein function in a yeast-based DNA damage response assay (PMID: 30851065) and in a mouse embryonic stem cell-based kinase assay (PMID: 34903604). This variant has been reported in an individual affected with breast cancer (PMID: 30535581) and in three brothers affected with prostate cancer (PMID: 34903604). This variant has been identified in 1/251408 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003993818	SCV000917234	likely pathogenic	Hereditary breast ovarian cancer syndrome	2024-02-15	criteria provided, single submitter	clinical testing	Variant summary: CHEK2 c.485A>G (p.Asp162Gly) results in a non-conservative amino acid change located in the Forkhead-associated (FHA) domain (IPR000253) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251408 control chromosomes. c.485A>G has been reported in the literature in a setting of whole exome sequencing in heterozygous individuals affected with prostate cancer from a single family (e.g. Boonen_2022), and in at least one individual at high risk for breast/ovarian cancer (e.g. Ciprano_2019). These data indicate that the variant may be associated with disease. Several publications report experimental evidence the variant leads to suggesting impaired protein function measured at ~10-30% of normal or kinase activity in all assays. These studies include a yeast-based growth assay (e.g. Delimitsou_2019), an mES-based cell assay measuring CHEK2 kinase activity (e.g. Boonen_2022), and CHEK2-complementation assays quantifying KAP1 phosphorylation and CHK2 autophosphorylation in human RPE1-CHEK2-knockout cells (e.g. Stolarova_2023). The following publications have been ascertained in the context of this evaluation (PMID: 30535581, 30851065, 34903604, 37449874). ClinVar contains an entry for this variant (Variation ID: 141314). Based on the evidence outlined above, the variant was classified as likely pathogenic.
Genetic Services Laboratory, University of Chicago	RCV000780181	SCV002070304	uncertain significance	not specified	2020-10-20	criteria provided, single submitter	clinical testing	DNA sequence analysis of the CHEK2 gene demonstrated a sequence change, c.485A>G, in exon 4 that results in an amino acid change, p.Asp162Gly. This sequence change does not appear to have been previously described in patients with CHEK2-related disorders and has been described in the gnomAD database in one individual with a low overall population frequency of 0.0004% (dbSNP rs587781652). The p.Asp162Gly change affects a highly conserved amino acid residue located in a domain of the CHEK2 protein that is known to be functional. The p.Asp162Gly substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Due to the lack of functional studies, the clinical significance of the p.Asp162Gly change remains unknown at this time.
Sema4, Sema4	RCV000129786	SCV002537605	uncertain significance	Hereditary cancer-predisposing syndrome	2021-12-30	criteria provided, single submitter	curation
Baylor Genetics	RCV000461401	SCV005058372	uncertain significance	Familial cancer of breast	2024-02-12	criteria provided, single submitter	clinical testing