CDH1 c.1214A>G, p.Asn405Ser

NM_004360.5:c.1214A>G

COSM308522

Classification Summary

Variant of Uncertain Significance (VUS)

The final classification of the CDH1 NM_004360.5:c.1214A>G (N405S) variant remains as a Variant of Uncertain Significance. Although PM2 and PM5 provide moderate evidence potentially supporting a pathogenic role, the supportive benign computational evidence from BP4 introduces conflicting data. In the absence of functional studies and additional supporting evidence, the variant is best classified as VUS.

Population Frequency

0.00278%

Low Frequency

ClinVar Classification

Uncertain Significance (VUS)

3 publications

REVEL Score

0.072

Likely Benign

COSMIC Recurrence

2 occurrences

No Criteria Applied

Classification Evidence

Very Strong (PVS)

None applied

Strong (PS/BS)

None applied

Moderate (PM/BA)

PM2 PM5

Supporting (PP/BP)

BP4

ClinVar COSMIC gnomAD OncoKB JAX-CKB SpliceAI

Created: 2025-04-14T13:54:56.180311

Detailed Information

Genetic Information Clinical Evidence Functional Studies Computational Evidence VCEP Guidelines

Genetic Information

Gene & Transcript Details

Gene

CDH1

Transcript

                                        
                                            NM_004360.5
                                        
                                                    MANE Select

Total Exons

Strand

Forward (+)

Reference Sequence

                                        NC_000016.9
                                    

Alternative Transcripts

ID	Status	Details
NM_004360.3	Alternative	16 exons \| Forward
NM_004360.4	Alternative	16 exons \| Forward
NM_004360.2	Alternative	16 exons \| Forward

Variant Details

HGVS Notation

NM_004360.5:c.1214A>G

Protein Change

N405S

Location

Exon 9 (Exon 9 of 16)

5' Exon Structure (16 total) 3'

Functional Consequence

Loss of Function

Related Variants

ClinVar reports other pathogenic variants at position 405: N405D

Alternate Identifiers

                                    COSM308522
                                

Variant interpretation based on transcript NM_004360.5

Clinical Evidence

Population Frequency

Global Frequency

0.00278%

Rare

Highest in Population

South Asian

0.00653%

Rare

Global: 0.00278%

South Asian: 0.00653%

0.0005%

0.001%

0.01%

0.05%

1%+

Allele Information

Total: 251488 Alt: 7 Homozygotes: 0

ACMG Criteria Applied

PM2

This variant is present in gnomAD (MAF= 0.00278%, 7/251488 alleles, homozygotes = 0) and at a higher frequency in the South Asian population (MAF= 0.00653%, 2/30616 alleles, homozygotes = 0). The variant is rare (MAF < 0.1%), supporting PM2 criterion application.

ClinVar 2025-04-14T13:52:42.850953

Classification

3 publications

Uncertain Significance (VUS)

Based on 7 submitter reviews in ClinVar

Submitter Breakdown

5 VUS

2 LB

Pathogenic

Likely Pathogenic

VUS

Likely Benign

Benign

Publications

3 publications

Show publication details

PMID: 25275298

Variant summary: CDH1 c.1214A>G (p.Asn405Ser) results in a conservative amino acid change located in the 3rd Cadherin domain of the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 3.2e-05 in 247626 control chromosomes. The observed variant frequency is approximately 1.14 fold above the estimated maximal expected allele frequency for a pathogenic variant in CDH1 causing Hereditary Diffuse Gastric Cancer phenotype (2.8e-05), suggesting the variant may be benign. The c.1214A>G variant has been reported in the literature in individuals affected with Hereditary Diffuse Gastric Cancer, however these reports do not provide unequivocal conclusions about an association of the variant with Hereditary Diffuse Gastric Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and all laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly benign.

PMID: 24728327

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

PMID: 25275298

The CDH1 c.1214A>G (p.Asn405Ser) variant has been reported in the published literature in individuals affected with colorectal cancer (PMID: 28135145 (2017)), and breast cancer (PMID: 33471991 (2021), see also LOVD (https://databases.lovd.nl/shared/variants/CDH1)). This variant has been identified in reportedly healthy individuals (PMID: 24728327 (2014), 29589180 (2019), 33471991 (2021), see also LOVD (https://databases.lovd.nl/shared/variants/CDH1)). The frequency of this variant in the general population, 0.000044 (5/113764 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant.

Publication Summary:

- **28492532**: This citation is associated with a submission by Labcorp Genetics, which classified the CDH1 variant as likely benign based on their variant classification method. The variant was evaluated using clinical testing. - **25275298**: This citation is linked to a submission by Women's Health and Genetics/Laboratory Corporation of America, LabCorp, which classified the variant as uncertain significance. The variant was found at a frequency slightly above the expected for a pathogenic variant, suggesting it may be benign. Clinical testing was used in the evaluation. - **28135145**: This citation is associated with multiple submissions, including those by LabCorp and Quest Diagnostics, which classified the variant as uncertain significance. The variant has been reported in individuals with colorectal cancer and healthy individuals, but its role in disease remains unclear. Clinical testing was used in the evaluation. - **22911296**: This citation is linked to submissions by LabCorp and Quest Diagnostics, which classified the variant as uncertain significance. The variant has been reported in individuals with hereditary diffuse gastric cancer, but its association with the disease is not definitive. Clinical testing was used in the evaluation. - **24728327**: This citation is associated with multiple submissions, including those by LabCorp, Ambry Genetics, and Quest Diagnostics, which classified the variant as uncertain significance or likely benign. The variant has been observed in healthy individuals, and its frequency in the population is not informative for pathogenicity. Clinical testing was used in the evaluation. - **29589180**: This citation is linked to submissions by Color Diagnostics and Ambry Genetics, which classified the variant as uncertain significance or likely benign. The variant has been reported in healthy individuals, and the available evidence is insufficient to determine its role in disease. Clinical testing was used in the evaluation. - **33471991**: This citation is associated with a submission by Quest Diagnostics, which classified the variant as uncertain significance. The variant has been reported in individuals with breast cancer and healthy individuals, but its clinical significance remains undetermined. Clinical testing was used in the evaluation.

Clinical Statement

This variant has been reported in ClinVar as Likely benign (2 clinical laboratories) and as Uncertain significance (5 clinical laboratories).

COSMIC

COSMIC ID

COSM308522

Recurrence

2 occurrences

PM1 Criteria

Not Applied

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Functional Domain

Cancer Hotspots

Hotspot Status

Not a hotspot

Domain Summary

This variant is not located in a mutational hotspot or critical domain (0 mutations).

Related Variants in This Domain

ClinVar reports other pathogenic variants at position 405: N405D

PM5 criterion applied: Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.

Functional Studies

Functional Impact

OncoKB JAX-CKB

Summary

The CDH1 N405S variant has not been functionally characterized.

Computational Evidence

Pathogenicity Predictions

REVEL Score

0.072

Likely Benign 0.0

Uncertain (Low) 0.2

Uncertain (Med) 0.5

Likely Pathogenic 0.75

REVEL scores ≥ 0.75 are considered strong evidence of pathogenicity (PP3)

Predictor Consensus

Mixed/VUS

PP3 Applied

Additional Predictors

Benign:

CADD: 0.03 polyphen_prediction: benign metasvm: T metalr: T primateai: T

Neutral: Show all

SpliceAI Scores Window: ±500bp

Effect Type	Score	Position
- Acceptor Loss	0.01	9 bp
- Donor Loss	0.0	9 bp
+ Acceptor Gain	0.01	1 bp
+ Donor Gain	0.0	106 bp

High impact (≥0.5)

Medium impact (0.2-0.49)

Low impact (<0.2)

VCEP Guidelines

Applied ACMG/AMP Criteria VCEP Guidelines

PVS1

PVS1 (Not Applied) Strength Modified

According to Standard ACMG guidelines, the rule for PVS1 is: 'Null variant (nonsense, frameshift, start-loss, splice site +/‐1 or 2) in a gene where loss‐of‐function is a known mechanism of disease.' The evidence for this variant shows that it is a missense change (N405S) rather than a null variant. Therefore, this criterion is not applied.

PS1

PS1 (Not Applied) Strength Modified

According to Standard ACMG guidelines, the PS1 rule is: 'Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.' The evidence for this variant does not indicate an identical amino acid change to a known pathogenic variant. Therefore, this criterion is not applied.

PS2

PS2 (Not Applied) Strength Modified

According to Standard ACMG guidelines, PS2 pertains to de novo variants with confirmed maternity and paternity in a patient with the disease. The evidence for this variant does not include de novo occurrence data. Therefore, this criterion is not applied.

PS3

PS3 (Not Applied) Strength Modified

According to PTEN Pre-processing guidelines, PS3 involves functional studies demonstrating a damaging impact. The rule/finding is: 'The CDH1 N405S variant has not been functionally characterized.' The evidence clearly shows that no functional data exists for this variant. Therefore, this criterion is not applied.

PS4

PS4 (Not Applied) Strength Modified

According to Standard ACMG guidelines, PS4 evaluates whether the prevalence of the variant in affected individuals is significantly increased compared with controls. The evidence for this variant does not include such case–control data. Therefore, this criterion is not applied.

PM1

PM1 (Not Applied) Strength Modified

According to Standard ACMG guidelines, PM1 applies to variants located in a mutational hot spot or critical functional domain without benign variation. The evidence provided does not specify that N405 resides in a region meeting these criteria. Therefore, this criterion is not applied.

PM2

PM2 (Moderate)

According to Standard ACMG guidelines, PM2 states: 'Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or ExAC.' The evidence for this variant shows an extremely low minor allele frequency (0.00278% overall and similarly low in specific populations) supporting the application of PM2 at a Moderate strength. Therefore, this criterion is applied at Moderate strength.

PM3

PM3 (Not Applied) Strength Modified

According to Standard ACMG guidelines, PM3 is used for detecting variants in trans with a pathogenic variant in autosomal recessive disorders. The evidence for this variant in CDH1 does not involve such segregation data. Therefore, this criterion is not applied.

PM4

PM4 (Not Applied) Strength Modified

According to Standard ACMG guidelines, PM4 relates to protein length changes due to in-frame deletions/insertions in non-repeat regions. In this case, the variant is a missense change and does not cause protein length alteration. Therefore, this criterion is not applied.

PM5

PM5 (Moderate)

According to Standard ACMG guidelines, PM5 is defined as: 'Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen.' The evidence for this variant indicates that although N405S is a novel change, there is knowledge of a different pathogenic missense change at the same amino acid residue. Therefore, this criterion is applied at Moderate strength.

PM6

PM6 (Not Applied) Strength Modified

According to Standard ACMG guidelines, PM6 applies to de novo variants without confirmation of parental origin when full criteria for PS2 are not met. The evidence for this variant does not include any de novo status information. Therefore, this criterion is not applied.

PP1

PP1 (Not Applied) Strength Modified

According to Standard ACMG guidelines, PP1 involves segregation evidence in families. The evidence for this variant does not include segregation data. Therefore, this criterion is not applied.

PP2

PP2 (Not Applied) Strength Modified

According to Standard ACMG guidelines, PP2 is applied to missense variants in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease. The provided evidence does not include sufficient context or statistical data regarding CDH1 to apply PP2. Therefore, this criterion is not applied.

PP3

PP3 (Not Applied) Strength Modified

According to Standard ACMG guidelines, PP3 involves multiple lines of computational evidence supporting a deleterious effect on the gene or gene product. Here, the computational evidence (including REVEL with a score of 0.07 and other in silico predictions) suggests a benign impact. Therefore, PP3 is not applied.

PP4

PP4 (Not Applied) Strength Modified

According to Standard ACMG guidelines, PP4 is used when the patient’s phenotype is highly specific for a disease with a single genetic etiology. The evidence for this variant does not include detailed phenotype information to support PP4. Therefore, this criterion is not applied.

PP5

PP5 (Not Applied) Strength Modified

According to Standard ACMG guidelines, PP5 refers to a reputable source reporting the variant as pathogenic without available evidence. The evidence here includes conflicting reports in ClinVar (both Likely benign and VUS), and PP5 is not independently supportive. Therefore, this criterion is not applied.

BA1

BA1 (Not Applied) Strength Modified

According to Standard ACMG guidelines, BA1 is a Stand Alone rule applied when the allele frequency is greater than 5% in population databases. The evidence for this variant reveals a much lower frequency (0.00278%), so BA1 is not applied.

BS1

BS1 (Not Applied) Strength Modified

According to Standard ACMG guidelines, BS1 is applied when the allele frequency is greater than expected for the disorder. The evidence shows an extremely low allele frequency, which does not support BS1. Therefore, this criterion is not applied.

BS2

BS2 (Not Applied) Strength Modified

According to Standard ACMG guidelines, BS2 is used when the variant is observed in a healthy adult for a disorder with full penetrance expected at an early age. The evidence does not include such observational data. Therefore, this criterion is not applied.

BS3

BS3 (Not Applied) Strength Modified

According to Standard ACMG guidelines, BS3 applies when well-established functional studies show no damaging effect on the gene or gene product. The evidence for this variant states that functional studies have not been conducted. Therefore, this criterion is not applied.

BS4

BS4 (Not Applied) Strength Modified

According to Standard ACMG guidelines, BS4 is used for lack of segregation with disease in affected family members. The evidence does not include segregation analysis data. Therefore, this criterion is not applied.

BP1

BP1 (Not Applied) Strength Modified

According to Standard ACMG guidelines, BP1 is applied when a missense variant is in a gene for which only truncating variants cause disease. The evidence for CDH1 does not support that only truncating variants cause disease, nor is there sufficient data to apply BP1. Therefore, this criterion is not applied.

BP2

BP2 (Not Applied) Strength Modified

According to Standard ACMG guidelines, BP2 applies when the variant is observed in trans with a pathogenic variant for a dominant disorder or in cis in recessive disorders. The evidence for this variant does not include such allelic data. Therefore, BP2 is not applied.

BP3

BP3 (Not Applied) Strength Modified

According to Standard ACMG guidelines, BP3 is used for in-frame deletions/insertions in repetitive regions without a known function. Since this is a missense change and there is no description of a repeat region, BP3 is not applicable. Therefore, this criterion is not applied.

BP4

BP4 (Supporting)

According to Standard ACMG guidelines, BP4 is: 'Multiple lines of computational evidence suggest no impact on gene or gene product.' The evidence for this variant includes a REVEL score of 0.07, corroborated by benign assessments from CADD, PolyPhen-2, and minimal splicing impact from SpliceAI. Therefore, BP4 is applied at a Supporting strength.

BP5

BP5 (Not Applied) Strength Modified

According to Standard ACMG guidelines, BP5 pertains to variants found in cases with an alternate molecular basis for the disease. The evidence for this variant does not include such information. Therefore, BP5 is not applied.

BP6

BP6 (Not Applied) Strength Modified

According to Standard ACMG guidelines, BP6 is applied when a reputable source reports the variant as benign without provided evidence. Although ClinVar submissions include Likely benign and VUS classifications, this does not provide conclusive benign evidence per se. Therefore, BP6 is not applied.

BP7

BP7 (Not Applied) Strength Modified

According to Standard ACMG guidelines, BP7 is generally used for synonymous variants with no predicted impact on splicing. Since the variant in question is a missense change (N405S), BP7 is not applicable. Therefore, this criterion is not applied.

LYFE SCIENCES

CDH1 c.1214A>G, p.Asn405Ser

Classification Summary

Genetic Information

Clinical Evidence

Functional Studies

Computational Evidence

VCEP Guidelines