NM_007194.4:c.1095+19G>A is an intronic variant in CHEK2 located at position +19 in intron 10. Computational evidence predicts no splicing impact: SpliceAI maximum delta score is 0.00 across all categories, consistent with a neutral intronic change (BP4_Supporting).1 A homozygous individual for this variant is observed in gnomAD v4.1, which is inconsistent with a highly penetrant autosomal dominant cancer predisposition variant (BS2_Supporting).2 ClinVar reports this variant as Likely benign by 9 clinical laboratories and Benign by 3 clinical laboratories (Variation ID: 371849), providing reputable source support for a benign interpretation (BP6_Supporting).3 The variant is observed at population frequencies of 0.017% (gnomAD v2.1) and 0.012% (gnomAD v4.1) with the highest subpopulation frequency of 0.237% in the Middle Eastern population (gnomAD v4.1), which approaches but does not exceed the BS1 threshold of 0.3%.4 No functional studies, segregation data, case-control enrichment, or variant-specific publications were identified for this variant. Three benign supporting criteria (BP4, BP6, BS2) are met. Under generic ACMG/AMP 2015 combination rules (PMID:25741868), two or more benign supporting criteria support a Likely Benign classification.5
CHEK2
Final classification
Likely Benign
BS2BP4BP6
CHEK2
c.1095+19G>A
p.?
This variant
NM_007194.4:c.1095+19G>A is an intronic variant in CHEK2 located at position +19 in intron 10.
Hereditary Breast, Ovarian and Pancreatic Cancer Specification v1.0.0 lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: BS2 supporting, BP4 supporting, BP6 supporting; combination = 3 supporting benign, which maps to Likely Benign.
Classification rationale
BS2BP4BP6
Likely Benign
CHEK2 c.1095+19G>A
BS2 + BP4 + BP6
→
Likely Benign
Gene diagram
· NM_007194.4 · variants mapped to exon structure
CHEK2
NM_007194.4
Fetching transcript structure from UCSC…
Applied criteria · 3 applied · 16 assessed
MetEvidence satisfies this criterion.
Not metEvaluated against available evidence; threshold not reached.
Not assessedApplies in principle, but no evidence was found to evaluate it.
N/ADoesn't apply to this variant type.
Applied · 3
Strength
Supporting
Moderate
Strong
Very strong
✓
BS2
supporting
Benign
A homozygous individual for NM_007194.4:c.1095+19G>A is observed in gnomAD v4.1 (1 homozygote among 1,542,484 alleles). CHEK2 is an autosomal dominant cancer predisposition gene where biallelic pathogenic variants would be expected to cause a severe or embryonic lethal phenotype. Observation of a homozygote in a population database is inconsistent with a highly penetrant pathogenic role and supports a benign interpretation.
gnomAD v4.1: 1 homozygous individual observed out of 1542484 alleles
✓
BP4
supporting
Benign
Computational evidence suggests no impact on splicing. SpliceAI predicts no splice alteration with a maximum delta score of 0.00 across all categories (acceptor gain, acceptor loss, donor gain, donor loss). The variant resides at position +19 in intron 10, well outside the canonical splice consensus, consistent with a neutral intronic change.
SpliceAI max delta = 0.00 (all categories: donor loss=0.00donor gain=0.00acceptor loss=0.00
✓
BP6
supporting
Benign
ClinVar reports NM_007194.4:c.1095+19G>A as Likely benign by 9 clinical laboratories and Benign by 3 clinical laboratories (Variation ID: 371849). Multiple independent clinical laboratories have reached a benign or likely benign classification, providing reputable source support for a benign interpretation.
ClinVar Variation ID 371849: Likely benign (9 labs)Benign (3 labs)12 clinical laboratories with concordant benign-leaning classification
Assessed · not applied
· 9 not met · 7 not assessed
Pathogenic
PS2
No de novo data are available for NM_007194.4:c.1095+19G>A.
PS3
No well-established in vitro or in vivo functional studies are available for NM_007194.4:c.1095+19G>A.
PS4
No case-control enrichment data are available for NM_007194.4:c.1095+19G>A.
PM1
NM_007194.4:c.1095+19G>A is a deep intronic variant located 19 bases downstream of exon 10.
PM2
PM2 requires absence or extremely low frequency in population databases.
PM6
No de novo data are available for NM_007194.4:c.1095+19G>A.
PP1
No cosegregation data are available for NM_007194.4:c.1095+19G>A.
PP3
Multiple lines of computational evidence do not support a deleterious effect.
PP4
No patient phenotype or family history data are available for independent assessment.
PP5
PP5 requires a reputable source to have recently reported the variant as pathogenic.
Benign
BA1
BA1 requires allele frequency >1% in population databases.
BS1
BS1 requires allele frequency greater than expected for disorder (>0.3% by non-VCEP threshold).
BS3
No well-established in vitro or in vivo functional studies demonstrating no damaging effect are available for NM_007194.4:c.1095+19G>A.
BS4
No segregation data are available to assess lack of cosegregation with disease in affected family members.
BP2
No phasing data are available to assess whether this variant has been observed in trans with a pathogenic CHEK2 variant.
BP5
No data are available indicating an alternate molecular basis for disease in a case carrying this variant.
N/A · 9
PVS1 · PS1 · PM3 · PM4 · PM5 · PP2 · BP1 · BP3 · BP7
Research & evidence
Population frequency · supports benign
gnomAD v4.1
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 0.000120585; MAF= 0.01206%, 186/1542484 alleles, homozygotes = 1) and has highest observed frequency in the Middle Eastern population (AF= 0.00236887; MAF= 0.23689%, 14/5910 alleles, homozygotes = 0); grpmax FAF= 0.0014315.
v2.1
This variant is present in gnomAD v2.1 (AF= 0.000166616; MAF= 0.01666%, 47/282086 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 0.00094827; MAF= 0.09483%, 29/30582 alleles, homozygotes = 0); grpmax FAF= 0.00067758.
🇨🇦 CA
Not available in gnomAD-Canada v1.0.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.012%
· 186 / 1,542,484
1 hom · FAF 0.14%
1 hom · FAF 0.14%
Middle Eastern 14 / 5,910 |
0.24% |
South Asian 81 / 89,542 |
0.09% 1 hom |
Remaining individuals 10 / 60,092 |
0.017% |
African/African American 7 / 73,590 |
0.0095% |
European (non-Finnish) 72 / 1,115,072 |
0.0065% |
Admixed American 2 / 59,900 |
0.0033% |
+ 4 not observed (European (Finnish), Amish, East Asian, Ashkenazi Jewish)
gnomAD v2.1
0.017%
· 47 / 282,086
0 hom · FAF 0.068%
0 hom · FAF 0.068%
South Asian 29 / 30,582 |
0.095% |
Remaining individuals 3 / 7,190 |
0.042% |
African/African American 4 / 24,906 |
0.016% |
European (non-Finnish) 9 / 128,796 |
0.007% |
Admixed American 2 / 35,374 |
0.0057% |
+ 3 not observed (Ashkenazi Jewish, East Asian, European (Finnish))
gnomAD Canada 🇨🇦
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
ClinVar
This variant has been reported in ClinVar as Likely benign (9 clinical laboratories) and as Benign (3 clinical laboratories). (ClinVarID = 371849)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).
Functional
No data
No calibrated functional assay or RNA evidence was identified for this variant.
COSMIC
Somatic evidence
COSMIC
This variant has not previously been reported in somatic cancers (COSMIC).
Hotspots
This variant does not lie in a statistically significant cancer hotspot.
Sources & reference links
Triaged references · 7 PMIDs not cited in assessment
25741868 ↗
Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.
CLINVAR
26389258 ↗
Cancer Genetics Risk Assessment and Counseling (PDQ®): Health Professional Version.
CLINVAR
31429903 ↗
Risk Assessment, Genetic Counseling, and Genetic Testing for BRCA-Related Cancer: US Preventive Services Task Force Recommendation Statement.
CLINVAR
35802134 ↗
ACMG SF v3.1 list for reporting of secondary findings in clinical exome and genome sequencing: A policy statement of the American College of Medical Genetics and Genomics (ACMG).
CLINVAR
28492532 ↗
Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.
CLINVAR