NM_007194.4:c.953G>A

CHEK2 · NP_009125.1:p.(Arg318His) · NM_007194.4

GRCh37: chr22:29095881 C>T · GRCh38: chr22:28699893 C>T

Gene: CHEK2 Transcript: NM_007194.4

Final call

VUS

PM2 supporting BP4 supporting

Variant details

Gene

CHEK2

Transcript

NM_007194.4

Protein

NP_009125.1:p.(Arg318His)

gnomAD AF

4.523109371263013e-05 (v4.1)

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

NM_007194.4:c.953G>A (p.Arg318His) is a missense variant in CHEK2 exon 9, located within the kinase domain. The variant has been observed at extremely low frequency in population databases (gnomAD v2.1: 13/282,864 alleles, AF=0.0046%; v4.1: 73/1,613,934 alleles, AF=0.0045%), consistent with PM2 at supporting level.

Computational in silico tools uniformly predict a benign effect: REVEL score 0.061, BayesDel score -0.127872, and SpliceAI max delta 0.00, supporting BP4 at supporting level.

Dong et al. (2003, PMID:12533788) identified this variant in 1 of 94 early-onset prostate cancer cases and 0 of 423 unaffected controls; it was not found in familial prostate cancer cases, and the single observation does not achieve statistical significance for PS4.

ClinVar reports this variant as Uncertain Significance (15 clinical laboratories) and Likely Benign (1 laboratory). No expert panel has classified this variant.

With PM2 (supporting pathogenic) and BP4 (supporting benign) applied, the evidence is balanced. The variant is classified as Variant of Uncertain Significance (VUS). Additional functional data (BS3/PS3) and case-control studies (PS4) are needed to resolve the classification.

Final determination: Generic ACMG/AMP 2015 fallback rules do not meet benign, likely benign, likely pathogenic, or pathogenic combination thresholds, so the variant is classified as Variant of Uncertain Significance.

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
PVS1	N/A	NM_007194.4:c.953G>A is a missense variant (p.Arg318His). PVS1 is restricted to null variants (nonsense, frameshift, canonical ±1,2 splice site, initiation codon, or exon-level deletions). This variant does not fall into any PVS1 bucket under the ClinGen SVI PVS1 decision tree (PMC6185798).	pvs1_variant_assessment pvs1_generic_framework
PS1	N/A	PS1 requires the same amino acid change (p.Arg318His) to have been established as pathogenic via a different underlying nucleotide change. No alternative nucleotide substitution causing p.Arg318His is known to be pathogenic.
PS2	Not assessed	No de novo occurrence data (with confirmed paternity and maternity) was identified in the reviewed evidence for NM_007194.4:c.953G>A.
PS3	Not assessed	Well-established in vitro functional studies demonstrating a damaging effect on CHEK2 protein function were not confirmed in full-text review. Exploratory evidence (PMID:16835864) suggested R318H does not impair kinase activity, but full text was unavailable for verification.
PS4	Not met	No statistically significant enrichment of NM_007194.4:c.953G>A was observed in affected individuals versus controls. In PMID:12533788 (Dong et al. 2003), the variant was detected in 1/94 early-onset prostate cancer cases and 0/423 unaffected controls, which does not reach statistical significance for this individual variant.	PMID:12533788
PS5	Not met	No reputable source has reported NM_007194.4:c.953G>A as pathogenic. ClinVar lists this variant as Uncertain Significance (15 clinical laboratories) and Likely Benign (1 clinical laboratory).	clinvar
PM1	Not met	Although p.Arg318His resides within the CHEK2 kinase domain (a well-established functional domain spanning residues ~220-486), the specific residue is not a recognized mutational hotspot, and the variant has been observed in population databases at low frequency. Cancer Hotspots did not identify this residue as statistically significant.	gnomad_v2 gnomad_v4
PM2	Met	NM_007194.4:c.953G>A is present at extremely low frequency in population databases: gnomAD v2.1 AF=0.0046% (13/282,864 alleles, 0 homozygotes) and gnomAD v4.1 AF=0.0045% (73/1,613,934 alleles, 0 homozygotes). Both are below the 0.1% threshold for PM2.	gnomad_v2 gnomad_v4
PM5	Not met	No pathogenic missense variant at the same amino acid residue (Arg318) with a different amino acid substitution was identified. Automated PM5 candidate search returned no results.	pm5_candidates
PM6	Not assessed	No de novo occurrence data (assumed or confirmed) was identified for NM_007194.4:c.953G>A.
PP1	Not met	No cosegregation data is available for this variant. In PMID:12533788, the variant was observed in a single early-onset prostate cancer case and was not identified in any of the 149 familial prostate cancer families screened.	PMID:12533788
PP2	Not met	PP2 requires a gene with a low rate of benign missense variation where missense variants are a common disease mechanism. CHEK2 has a substantial number of missense variants observed in the general population (gnomAD missense Z-score and constraint metrics are not strongly missense-depleted), and truncating variants are the predominant established pathogenic mechanism.	gnomad_v2
PP3	Not met	Multiple lines of in silico evidence predict a benign effect: REVEL score 0.061 (below the 0.5 pathogenicity threshold), BayesDel score -0.127872 (negative score indicates benign), and SpliceAI max delta 0.00 (no predicted splice impact). All available computational tools support a neutral effect.	revel bayesdel spliceai
PP4	Not assessed	No patient phenotype or family history data specific to the index case carrying NM_007194.4:c.953G>A was provided for review.
PP5	Not met	No reputable source has reported NM_007194.4:c.953G>A as pathogenic. ClinVar reports this variant as Uncertain Significance by 15 clinical laboratories and Likely Benign by 1 laboratory (Myriad Genetics). No expert panel or practice guideline classifies this variant as pathogenic.	clinvar
BA1	Not met	The maximum allele frequency in gnomAD v2.1 is 0.0046% (grpmax FAF 3.89e-05), far below the BA1 threshold of 1%.	gnomad_v2 gnomad_v4
BS1	Not met	The allele frequency in gnomAD is 0.0046% (v2.1) and 0.0045% (v4.1), far below the BS1 threshold of 0.3%.	gnomad_v2 gnomad_v4
BS2	Not met	While NM_007194.4:c.953G>A is observed in gnomAD (a general population cohort that includes healthy individuals), the frequency is extremely low (AF ~0.0046%) and does not constitute strong evidence for BS2, which requires observation in healthy adults at a frequency inconsistent with full penetrance for a dominant disorder.	gnomad_v2
BS3	Not assessed	Well-established functional studies showing no damaging effect on CHEK2 protein function were not confirmed in full-text review. Exploratory evidence (PMID:16835864, Roeb et al. 2006) reported that R318H does not impair CHEK2 kinase activity, but full text was unavailable for independent verification. If confirmed, this would support BS3 at the supporting or moderate level.
BS4	Not met	No cosegregation or nonsegregation data are available for NM_007194.4:c.953G>A. The variant was not identified in familial prostate cancer cases in PMID:12533788, precluding segregation analysis.	PMID:12533788
BP1	Not met	BP1 applies to missense variants in genes where primarily truncating variants cause disease. CHEK2 has multiple well-established pathogenic missense variants (e.g., p.Ile157Thr, p.Arg145Trp, p.Ser428Phe) in addition to truncating variants. Missense changes are a recognized disease mechanism in CHEK2, so BP1 does not apply.	PMID:12533788
BP2	Not assessed	No phase data (in cis or in trans with a known pathogenic variant) is available for NM_007194.4:c.953G>A.
BP4	Met	Multiple lines of computational evidence support a benign effect. REVEL score is 0.061 (below pathogenicity threshold), BayesDel score is -0.127872 (negative = benign), and SpliceAI predicts no splice impact (max delta = 0.00). All available in silico tools are concordant in predicting a neutral effect.	revel bayesdel spliceai
BP5	Not assessed	No data was available regarding an alternative molecular basis for disease in a proband carrying NM_007194.4:c.953G>A.
BP6	Not met	One clinical laboratory (Myriad Genetics, SCV005896018) classified this variant as Likely Benign, but this constitutes a single submitter. BP6 requires a reputable source (e.g., expert panel, practice guideline) reporting the variant as benign with unavailable evidence. No such source exists.	clinvar
BP7	N/A	NM_007194.4:c.953G>A is a missense variant (p.Arg318His), not a synonymous variant. BP7 applies only to synonymous variants with no predicted splice impact.

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