NM_007194.4:c.731A>G

CHEK2 · NP_009125.1:p.(Lys244Arg) · NM_007194.4

GRCh37: chr22:29107958 T>C · GRCh38: chr22:28711970 T>C

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.(Lys244Arg)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

The CHEK2 c.731A>G (p.Lys244Arg) variant has not been observed in somatic cancers in COSMIC and has been reported in ClinVar as uncertain significance by 7 clinical laboratories.

The variant is present at very low frequency in gnomAD, with AF 1.06e-05 in v2.1 and 9.29e-06 in v4.1, and no homozygotes were observed, which supports rarity.

In silico data argue against a deleterious effect, with REVEL 0.062 and SpliceAI predicting no significant splice impact (max delta score 0.00).

Final determination: With one supporting pathogenic criterion (PM2_supporting) and one supporting benign criterion (BP4_supporting), the criteria do not meet ACMG/AMP combination thresholds for either likely pathogenic or likely benign; therefore the variant is classified as 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	Missense substitution p.(Lys244Arg) does not represent a predicted loss-of-function variant.	prefetch.json case_summary.json
PS1	Not assessed	No evidence was retrieved showing another nucleotide change that produces the same amino acid substitution and is established as pathogenic/likely pathogenic.
PS2	Not assessed	No confirmed de novo data were retrieved.
PS3	Not assessed	Functional publications were cited in ClinVar/literature triage, but no validated assay result for CHEK2 p.(Lys244Arg) was extracted with sufficient detail to support damaging functional evidence.	literature_pass.json case_summary.json
PS4	Not assessed	The variant has been reported in ClinVar, but case-control enrichment or a case count meeting ACMG/AMP evidence thresholds was not retrieved.	case_summary.json literature_pass.json
PM1	Not met	Cancer Hotspots did not identify residue K244 as a statistically significant hotspot, and no mutational hotspot or well-established critical functional residue evidence was retrieved.	evidence.json case_summary.json
PM2	Met	The variant is present at very low frequency in population databases (gnomAD v2.1 AF 1.06e-05, 3/282782; gnomAD v4.1 AF 9.29e-06, 15/1613930) with no homozygotes observed, supporting rarity.	case_summary.json evidence.json
PM3	N/A	PM3 is intended for recessive disorders with trans observations and is not applicable to the autosomal dominant CHEK2-related cancer predisposition framework used here.	prefetch.json
PM4	N/A	This is a missense substitution rather than a protein length-changing variant.	prefetch.json
PM5	Not assessed	No evidence was retrieved showing a different pathogenic missense change at codon 244.
PM6	Not assessed	No assumed de novo observations were retrieved.
PP1	Not assessed	No segregation data were retrieved.
PP2	Not assessed	No gene-level missense constraint or pathogenic missense enrichment evidence specific enough to support PP2 was retrieved.
PP3	Not met	Available computational evidence does not support a deleterious effect: REVEL is low (0.062) and SpliceAI predicts no significant splice impact (max delta 0.00).	prefetch.json evidence.json case_summary.json
PP4	Not assessed	No phenotype or family history data were provided to support a highly specific CHEK2-related presentation.
PP5	N/A	PP5 is deprecated and was not used for adjudication.	case_summary.json
BA1	Not met	Population frequency is far below stand-alone benign thresholds.	case_summary.json
BS1	Not met	Population frequency is too low to support a benign frequency-based criterion.	case_summary.json
BS2	Not assessed	No evidence was retrieved showing the variant in healthy adults at a frequency or context sufficient for BS2.	case_summary.json
BS3	Not assessed	No well-established functional study demonstrating normal CHEK2 protein function for p.(Lys244Arg) was extracted.	literature_pass.json case_summary.json
BS4	Not assessed	No segregation data showing lack of cosegregation were retrieved.
BP1	Not assessed	No gene-specific evidence was retrieved to support that truncating variants predominate and that missense variation is generally not disease-causing in CHEK2.
BP2	Not assessed	No allelic phase or co-occurrence data were retrieved.
BP3	N/A	This is not an in-frame insertion/deletion in a repetitive region.	prefetch.json
BP4	Met	Computational evidence supports a benign effect: REVEL is low at 0.062 and SpliceAI predicts no significant splice impact with max delta score 0.00.	prefetch.json evidence.json case_summary.json
BP5	Not assessed	No alternate molecular explanation for the phenotype was retrieved.
BP6	N/A	BP6 is deprecated and was not used for adjudication.	case_summary.json
BP7	N/A	BP7 applies to synonymous or certain intronic variants and is not applicable to this missense substitution.	prefetch.json

Disclaimer: The content and results provided by LYFE Sciences are for research and educational purposes only and must not be used as a substitute for professional medical judgment, diagnosis, or treatment. Always consult a qualified healthcare professional before making any clinical decisions.