22-28696960-G-T
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong
The NM_007194.4(CHEK2):c.1036C>A(p.Arg346Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,726 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Consequence
NM_007194.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00 AC: 0AN: 152030Hom.: 0 Cov.: 33 FAILED QC
GnomAD4 exome AF: 6.85e-7 AC: 1AN: 1460726Hom.: 0 Cov.: 29 AF XY: 0.00000138 AC XY: 1AN XY: 726746
GnomAD4 genome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0AN: 152030Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74258
ClinVar
Submissions by phenotype
Familial cancer of breast Uncertain:1
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. 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. ClinVar contains an entry for this variant (Variation ID: 645557). This missense change has been observed in individual(s) with clinical features of CHEK2-related conditions (PMID: 29470806). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with serine, which is neutral and polar, at codon 346 of the CHEK2 protein (p.Arg346Ser). -
Hereditary cancer-predisposing syndrome Uncertain:1
The p.R346S variant (also known as c.1036C>A), located in coding exon 9 of the CHEK2 gene, results from a C to A substitution at nucleotide position 1036. The arginine at codon 346 is replaced by serine, an amino acid with dissimilar properties. This variant was observed in a study of 1010 unrelated Indian patients with breast and/or ovarian cancer (Singh J et al. Breast Cancer Res. Treat., 2018 Jul;170:189-196). This alteration was reported as functionally impaired 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. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at