Variant classification summary

NM_007194.4:c.1427C>T

CHEK2 · NP_009125.1:p.(Thr476Met) · NM_007194.4

GRCh37: chr22:29090054 G>A · GRCh38: chr22:28694066 G>A

Gene: CHEK2 Transcript: NM_007194.4

Final call

Likely Benign

BS1 supporting benign BP4 supporting benign

Variant details

Gene

CHEK2

Transcript

NM_007194.4

Protein

NP_009125.1:p.(Thr476Met)

gnomAD AF

0.00040353557316463376 (v4.1)

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

NM_007194.4:c.1427C>T (p.Thr476Met) is a missense variant in CHEK2 exon 13, located within the protein kinase domain.

2

This variant is present in gnomAD v2.1 at an allele frequency of 0.0313% (83/265,178 alleles, 0 homozygotes) and in gnomAD v4.1 at 0.0404% (644/1,595,894 alleles) including one homozygous carrier in the Middle Eastern subpopulation (AF 0.407%).

3

The variant is reported in ClinVar with conflicting classifications: Uncertain significance (29 clinical laboratories), Likely pathogenic (22 laboratories), and single submissions of Pathogenic, Likely benign, Likely risk allele, and Established risk allele (ClinVar Variation ID: 128060).

4

The Middle Eastern subpopulation allele frequency of 0.407% in gnomAD v4.1 exceeds the BS1 threshold of 0.3%, which is higher than expected for a pathogenic CHEK2 variant (BS1_Supporting).

5

Multiple in silico tools predict a benign effect: BayesDel score 0.096 is in the benign range and SpliceAI max delta 0.03 predicts no splicing alteration. REVEL score 0.445 is borderline (BP4_Supporting).

6

The variant was identified as a novel missense substitution in a Bulgarian breast cancer cohort (PMID:22862163, Angelova et al. 2012, n=145 patients), but no case-control statistics or functional characterization were provided.

7

No well-established functional assay data, segregation studies, or case-control analyses are available to confirm or refute pathogenicity for this specific variant.

8

The presence of a homozygous carrier in gnomAD v4.1 is notable for an autosomal dominant cancer predisposition gene, though formal BS2 criteria are not met because CHEK2-related cancer risk has incomplete penetrance and adult onset, and the phenotype of the homozygous individual is unknown.

9

Overall, the available evidence includes one supporting benign criterion (BS1) and one supporting benign criterion (BP4), with no pathogenic criteria met. The evidence favors a benign interpretation but remains insufficient for a definitive classification.

Final determination: Generic ACMG/AMP 2015 fallback rules support a Likely Benign classification because either one strong benign criterion plus one supporting benign criterion, or at least two supporting benign criteria, are present.

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.1427C>T is a missense variant (p.Thr476Met), not a null variant (nonsense, frameshift, or canonical splice site). PVS1 is not applicable for missense substitutions per ACMG/AMP guidelines.	pvs1_variant_assessment
PS1	Not assessed	No known pathogenic variant at the same amino acid position (Thr476) with a different nucleotide change has been identified. Without a same-residue pathogenic comparator, PS1 cannot be applied.
PS2	Not assessed	No documented de novo occurrence of NM_007194.4:c.1427C>T has been identified in the literature or databases. PS2 requires confirmed de novo status with parental testing.
PS3	Not assessed	No well-established functional assay data demonstrating a damaging effect for p.Thr476Met has been confirmed. PMID:22419737 tested 25 CHEK2 missense variants in a yeast-based DNA damage response assay, but whether p.Thr476Met was among those tested could not be verified from the available abstract or data sources.
PS4	Not met	No case-control study demonstrating statistically significant enrichment of NM_007194.4:c.1427C>T in affected individuals versus controls has been identified. PMID:22862163 reported the variant in Bulgarian breast cancer patients but without case-control comparison or odds ratio. The variant is present in gnomAD population databases at low frequency, precluding a simple absence-based case enrichment argument.	gnomad_v2 gnomad_v4
PS5	Not assessed	No reputable source has independently and definitively classified this variant as pathogenic with evidence that can be verified. ClinVar classification is predominantly Uncertain significance with conflicting submissions from multiple laboratories.	clinvar
PM1	Not met	Although p.Thr476Met is located within the CHEK2 protein kinase domain (residues ~229-507), a critical functional domain, the presence of a homozygous carrier in gnomAD v4.1 (Middle Eastern population) and a subpopulation allele frequency of 0.407% indicate that this residue tolerates variation in the general population. PM1 requires that the domain have low tolerance for benign variation, which is not supported by the population data for this specific residue.	gnomad_v4
PM2	Not met	While gnomAD v2.1 overall allele frequency (0.0313%) is below the generic PM2 threshold of 0.1%, gnomAD v4.1 data reveal a higher frequency (0.0404% overall; 0.407% in the Middle Eastern subpopulation) including one homozygous carrier. This population presence, particularly the homozygote, does not support absence from population databases as required for PM2. The variant is not sufficiently rare to meet PM2 when considering the larger v4.1 dataset.	gnomad_v2 gnomad_v4
PM5	N/A	No alternative missense change at the same amino acid residue (Thr476) classified as pathogenic was identified. The automated PM5 candidate harvest found zero same-residue comparator variants.	pm5_candidates
PM6	Not assessed	No assumed de novo occurrence (unconfirmed parentage) has been reported for this variant. PM6 requires observation of a de novo event without confirmation of parental relationships.
PP1	Not assessed	No cosegregation data have been published for NM_007194.4:c.1427C>T with disease in multiple affected family members. PP1 requires demonstration of variant cosegregation with disease phenotype.
PP2	Not assessed	PP2 requires a low rate of benign missense variation in the gene and that missense variants are a common mechanism of disease. CHEK2 missense constraint metrics (e.g., Z-score) were not available in the current data sources to determine whether the gene meets the threshold for PP2 application.
PP3	Not met	Multiple computational tools do not support a deleterious effect. REVEL score 0.445 is below the commonly used pathogenic threshold of 0.5. BayesDel score 0.096 is in the benign range (threshold <0.13 for benign). SpliceAI max delta score 0.03 predicts no splicing alteration. No HCI prior probability is available for CHEK2. The preponderance of in silico evidence does not support PP3.	revel bayesdel spliceai
PP4	Not assessed	No patient-specific phenotype or family history data were provided for this case. PP4 requires that the patient's phenotype or family history is highly specific for the disease gene in question.
PP5	Not met	No reputable source has definitively classified this variant as pathogenic. ClinVar classification is predominantly Uncertain significance with conflicting submissions (29 VUS vs. 22 Likely pathogenic vs. 1 Pathogenic). The lack of consensus and the predominance of VUS classifications do not support PP5.	clinvar
BA1	Not met	The highest observed population allele frequency is 0.407% in the gnomAD v4.1 Middle Eastern subpopulation, which does not exceed the 1% threshold required for BA1. The variant is not sufficiently common to be considered a benign polymorphism by allele frequency alone.	gnomad_v4
BS1	Met	The gnomAD v4.1 Middle Eastern subpopulation allele frequency of 0.407% exceeds the BS1 threshold of 0.3% for a dominant disorder. This frequency is higher than expected for a pathogenic CHEK2 variant with moderate penetrance, particularly given the presence of a homozygous carrier in the same subpopulation.	gnomad_v4
BS2	Not met	Although one homozygous carrier is present in gnomAD v4.1 (Middle Eastern population), BS2 requires observation in a healthy adult with a disorder expected to have full penetrance at an early age. CHEK2-related cancer predisposition has incomplete penetrance and adult onset, and gnomAD does not provide phenotype data to confirm the homozygous individual is cancer-free. The homozygote finding is suggestive but does not strictly meet the BS2 requirement for this adult-onset, incompletely penetrant condition.	gnomad_v4
BS3	Not assessed	No well-established functional assay demonstrating a benign effect for p.Thr476Met has been identified. PMID:22419737 tested 25 CHEK2 missense alleles, some of which exhibited wild-type-like DNA damage response, but whether p.Thr476Met was among those and which functional category it fell into cannot be determined from the available data.
BS4	Not assessed	No segregation data demonstrating lack of cosegregation with disease have been published for this variant. BS4 requires observation that the variant does not segregate with disease in affected families.
BP1	N/A	CHEK2 disease is caused by both protein-truncating and missense variants. PMID:21244692 demonstrated that rare, evolutionarily unlikely missense substitutions in CHEK2 confer breast cancer risk equivalent to protein-truncating variants. Missense variants are an established disease mechanism in CHEK2, so BP1 does not apply.
BP2	Not assessed	No observation of this variant in trans with a known pathogenic CHEK2 variant (in a recessive model) or in cis with a pathogenic variant (in a dominant model) has been reported. BP2 requires specific phase information.
BP4	Met	Multiple lines of computational evidence suggest a benign effect. BayesDel score 0.096 falls within the benign range. SpliceAI max delta score 0.03 predicts no splicing alteration. REVEL score 0.445 is borderline and does not independently predict pathogenicity. Two of three computational tools support a benign interpretation.	bayesdel spliceai revel
BP5	Not assessed	No evidence is available indicating that this variant was found in a case with an alternate molecular basis for disease. BP5 requires identification of a different causative pathogenic variant in the same individual.
BP6	Not met	No reputable source has definitively classified this variant as benign. One ClinVar submission from Myriad Genetics classifies as Likely benign (SCV004020185), but this is a single flagged submission and does not constitute a reputable consensus. The majority of ClinVar submissions report Uncertain significance.	clinvar
BP7	N/A	NM_007194.4:c.1427C>T is a missense variant (p.Thr476Met), not a synonymous or intronic variant. BP7 applies only to synonymous variants with no predicted splicing impact.

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.