NM_004360.5:c.1266A>G (p.Gln422=) is a synonymous variant in CDH1 exon 9. SpliceAI predicts no impact on splicing (max delta score = 0.00).1 BP7 (supporting) is applied per CDH1 CSPEC v3.1: synonymous variant without requirement for conservation prediction.2 The variant is present in gnomAD at very low frequency: 3/251,488 alleles in v2.1 (0.00119%) and 15/1,614,208 alleles in v4.1 (0.00093%), with no homozygotes.3 In ClinVar, this variant is classified as Likely benign by 7 clinical laboratories and as Benign by 1 clinical laboratory (ClinVar Variation ID: 185874, 1-star review status).4 No pathogenic criteria are met. Only BP7 (supporting benign) is applicable. With a single supporting benign criterion, the formal ACMG/AMP classification is Variant of Uncertain Significance; however, the clinical consensus from 8 diagnostic laboratories supports a Likely benign interpretation for this synonymous variant with no predicted splice impact.
CDH1
Final classification
VUS
CDH1 c.1266A>G · p.Gln422=
CDH1
NM_004360.5:c.1266A>G (p.Gln422=) is a synonymous variant in CDH1 exon 9.
ClinGen CDH1 Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 3.1 v3.1 lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: BP7 supporting; combination = 1 supporting benign, which maps to VUS.
Classification rationale
BP7
VUS
CDH1 c.1266A>G
BP7
→
VUS
Gene diagram
· NM_004360.5 · variants mapped to exon structure
CDH1
NM_004360.5
Fetching transcript structure from UCSC…
Applied criteria · 1 applied · 16 assessed
Applied · 1
Strength
Supporting
Moderate
Strong
Very strong
✓
BP7
supporting
Benign
NM_004360.5:c.1266A>G is a synonymous variant (p.Gln422=) in exon 9. Under CDH1 CSPEC v3.1, BP7 applies to synonymous variants without requiring a conservation prediction. SpliceAI predicts no splice impact (max delta = 0.00), and the variant is located 54 nucleotides upstream of the exon 9 donor splice site, well outside the splice consensus region.
Synonymous variant p.Gln422=CDH1 CSPEC BP7 does not require conservation predictionSpliceAI delta = 0.00
Assessed · not applied
Pathogenic
PVS1
NM_004360.5:c.1266A>G is a synonymous variant (p.Gln422=) and does not meet the PVS1 null-variant criteria under the CDH1 CSPEC v3.1 decision tree, which covers nonsense, frameshift, canonical ±1,2 splice site, initiation codon, and exon deletion variants.
PS2
No de novo observations with confirmed maternity and paternity meeting HDGC individual phenotype criteria are available for this variant.
PS3
Under CDH1 CSPEC v3.1, PS3 is restricted to RNA assays demonstrating abnormal transcripts.
PS4
No families meeting HDGC criteria have been reported for this variant.
PM2
The variant is present in gnomAD at low frequency.
PM6
No assumed de novo observations (without parental confirmation) meeting HDGC individual phenotype criteria are available for this variant.
PP1
No cosegregation data with informative meioses are available for this variant.
PP3
Under CDH1 CSPEC v3.1, PP3 requires at least three in silico splicing predictors in agreement.
Benign
BA1
The CDH1 CSPEC BA1 threshold is MAF >0.2%.
BS1
The CDH1 CSPEC BS1 threshold is MAF >0.1%.
BS2
BS2 requires ≥10 individuals without gastric cancer, DGC, SRC tumors, or LBC and whose families do not suggest HDGC.
BS3
Under CDH1 CSPEC v3.1, BS3 requires functional RNA studies demonstrating no impact on transcript composition.
BS4
No segregation data are available to assess lack of segregation in affected family members.
BP2
No evidence of the variant in trans with a known pathogenic variant or in a homozygous state in an individual without HDGC-related cancer history.
BP4
Under CDH1 CSPEC v3.1, BP4 requires at least three in silico splicing predictors in agreement.
BP5
BP5 applies when a pathogenic/likely pathogenic variant is identified in an alternate gene known to cause HDGC (currently only CTNNA1).
N/A · 8
PS1 · PM1 · PM5 · PP2 · PP4 · PP5 · BP1 · BP6
Research & evidence
Population frequency
gnomAD v4.1
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 9.29248e-06; MAF= 0.00093%, 15/1614208 alleles, homozygotes = 0) and has highest observed frequency in the Middle Eastern population (AF= 0.000329924; MAF= 0.03299%, 2/6062 alleles, homozygotes = 0); grpmax FAF= 5.818e-05.
v2.1
This variant is present in gnomAD v2.1 (AF= 1.1929e-05; MAF= 0.00119%, 3/251488 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 3.26627e-05; MAF= 0.00327%, 1/30616 alleles, homozygotes = 0); grpmax FAF= 2.92e-06.
🇨🇦 CA
Absent from gnomAD-Canada v1.0.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.00093%
· 15 / 1,614,208
0 hom · FAF 0.0058%
0 hom · FAF 0.0058%
Middle Eastern 2 / 6,062 |
0.033% |
South Asian 3 / 91,078 |
0.0033% |
European (non-Finnish) 10 / 1,180,024 |
0.00085% |
+ 7 not observed (Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Ashkenazi Jewish, African/African American)
gnomAD v2.1
0.0012%
· 3 / 251,488
0 hom · FAF 0.00029%
0 hom · FAF 0.00029%
South Asian 1 / 30,616 |
0.0033% |
European (non-Finnish) 2 / 113,764 |
0.0018% |
+ 6 not observed (African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals)
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 (7 clinical laboratories) and as Benign (1 clinical laboratory). (ClinVarID = 185874)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).
Functional
Unknown Oncogenic Effect
OncoKB identified curated literature and non-variant-specific oncogenicity context for review; listed oncogenicity label: Unknown Oncogenic Effect.
COSMIC
Cancer hotspots
Somatic evidence
Not in COSMIC / hotspots
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV55734749, n = 1 times).
Hotspots
This variant does not lie in a statistically significant hotspot.
Sources & reference links
9Sources
Triaged references · 8 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
26467025 ↗
A Standardized DNA Variant Scoring System for Pathogenicity Assessments in Mendelian Disorders.
CLINVAR
20065170 ↗
American Society of Clinical Oncology policy statement update: genetic and genomic testing for cancer susceptibility.
CLINVAR
25394175 ↗
A practice guideline from the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors: referral indications for cancer predisposition assessment.
CLINVAR
26324357 ↗
American Society of Clinical Oncology Policy Statement Update: Genetic and Genomic Testing for Cancer Susceptibility.
CLINVAR
29939840 ↗
Recommendations on Disease Management for Patients With Advanced Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer and Brain Metastases: ASCO Clinical Practice Guideline Update.
CLINVAR
28492532 ↗
Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.
CLINVAR