16-68801670-T-G

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

This summary comes from the ClinGen Evidence Repository: The c.164T>G (p.Val55Gly) variant has been observed in >10 (113) individuals without a diagnosis of diffuse gastric cancer, signet ring tumor or lobular breast cancer and whose family histories do not suggest HDGC (BS2; SCV000321508.8, SCV000153979.11). In summary, the clinical significance of this variant is classified as likely benign based on BS2 alone, as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): BS2. LINK:https://erepo.genome.network/evrepo/ui/classification/CA157980/MONDO:0007648/007

Frequency

Genomes: 𝑓 0.000072 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00011 ( 0 hom. )

Consequence

CDH1
NM_004360.5 missense, splice_region

Scores

8
9
2
Splicing: ADA: 0.5035
2

Clinical Significance

Likely benign reviewed by expert panel U:7B:9O:1

Conservation

PhyloP100: 6.02
Variant links:
Genes affected
CDH1 (HGNC:1748): (cadherin 1) This gene encodes a classical cadherin of the cadherin superfamily. Alternative splicing results in multiple transcript variants, at least one of which encodes a preproprotein that is proteolytically processed to generate the mature glycoprotein. This calcium-dependent cell-cell adhesion protein is comprised of five extracellular cadherin repeats, a transmembrane region and a highly conserved cytoplasmic tail. Mutations in this gene are correlated with gastric, breast, colorectal, thyroid and ovarian cancer. Loss of function of this gene is thought to contribute to cancer progression by increasing proliferation, invasion, and/or metastasis. The ectodomain of this protein mediates bacterial adhesion to mammalian cells and the cytoplasmic domain is required for internalization. This gene is present in a gene cluster with other members of the cadherin family on chromosome 16. [provided by RefSeq, Nov 2015]

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

BS2
For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CDH1NM_004360.5 linkc.164T>G p.Val55Gly missense_variant, splice_region_variant Exon 3 of 16 ENST00000261769.10 NP_004351.1 P12830-1A0A0U2ZQU7B3GN61

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
CDH1ENST00000261769.10 linkc.164T>G p.Val55Gly missense_variant, splice_region_variant Exon 3 of 16 1 NM_004360.5 ENSP00000261769.4 P12830-1

Frequencies

GnomAD3 genomes
AF:
0.0000723
AC:
11
AN:
152158
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000724
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000118
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000239
AC:
6
AN:
251390
Hom.:
0
AF XY:
0.0000221
AC XY:
3
AN XY:
135870
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000528
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.000110
AC:
160
AN:
1460268
Hom.:
0
Cov.:
32
AF XY:
0.000110
AC XY:
80
AN XY:
726566
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.000140
Gnomad4 OTH exome
AF:
0.0000663
GnomAD4 genome
AF:
0.0000723
AC:
11
AN:
152158
Hom.:
0
Cov.:
32
AF XY:
0.0000673
AC XY:
5
AN XY:
74348
show subpopulations
Gnomad4 AFR
AF:
0.0000724
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000118
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000116
Hom.:
0
Bravo
AF:
0.0000718
TwinsUK
AF:
0.000270
AC:
1
ALSPAC
AF:
0.00
AC:
0
ExAC
AF:
0.0000165
AC:
2
EpiCase
AF:
0.000109
EpiControl
AF:
0.0000593

ClinVar

Significance: Likely benign
Submissions summary: Uncertain:7Benign:9Other:1
Revision: reviewed by expert panel
LINK: link

Submissions by phenotype

Hereditary diffuse gastric adenocarcinoma Uncertain:2Benign:2
Feb 04, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Aug 01, 2022
European Reference Network on Genetic Tumour Risk Syndromes (ERN-GENTURIS), i3s - Instituto de Investigação e Inovação em Saúde, University of Porto
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

BS2 (PMID: 30311375) -

May 19, 2017
Counsyl
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Mar 06, 2023
Myriad Genetics, Inc.
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk. -

not specified Uncertain:1Benign:2Other:1
Dec 05, 2019
Genetic Services Laboratory, University of Chicago
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Sep 19, 2013
ITMI
Significance: not provided
Review Status: no classification provided
Collection Method: reference population

- -

Mar 04, 2025
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Nov 25, 2024
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Variant summary: CDH1 c.164T>G (p.Val55Gly) results in a non-conservative amino acid change located in the Cadherin prodomain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. Consensus agreement among computation tools predict no significant impact on normal splicing. Lack of impact on splicing was confirmed by RNA sequencing studies (Karam_2019). The variant allele was found at a frequency of 0.00011 in 1612426 control chromosomes, predominantly at a frequency of 0.00014 within the Non-Finnish European subpopulation in the gnomAD v4 database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 5 fold of the estimated maximal expected allele frequency for a pathogenic variant in CDH1 causing Hereditary Diffuse Gastric Cancer phenotype (2.8e-05). c.164T>G has been reported in the literature in individuals affected with colon cancer, breast cancer cases and controls and recurrent pregnancy loss (Yurgelun_2017, DeRycke_2017, Quintero-Ronderos_2017, Dorling_2021). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Diffuse Gastric Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 28944238, 33471991, 31642931, 29016666, 28135145). ClinVar contains an entry for this variant (Variation ID: 132769). Based on the evidence outlined above, the variant was classified as likely benign. -

Hereditary cancer-predisposing syndrome Uncertain:1Benign:2
Jan 12, 2022
Sema4, Sema4
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: curation

- -

Oct 29, 2018
Ambry Genetics
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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. -

Feb 25, 2025
Color Diagnostics, LLC DBA Color Health
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

not provided Uncertain:1Benign:1
Feb 23, 2024
Quest Diagnostics Nichols Institute San Juan Capistrano
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The CDH1 c.164T>G (p.Val55Gly) variant has been reported in the published literature in individuals with colorectal cancer (PMIDs: 28944238 (2017), 28135145 (2017)) and breast cancer (PMID:24969172 (2014)), as well as in one family with a history of both gastric cancer and breast cancer (PMID: 36436516 (2023)). Additionally, this variant was seen in a cohort of reportedly healthy individuals (PMID: 24728327 (2014)). The frequency of this variant in the general population, 0.000054 (7/129106 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 damaging. Based on the available information, we are unable to determine the clinical significance of this variant. -

Sep 01, 2022
GeneDx
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

See Variant Classification Assertion Criteria. -

CDH1-related diffuse gastric and lobular breast cancer syndrome Benign:2
Aug 17, 2023
ClinGen CDH1 Variant Curation Expert Panel
Significance: Likely benign
Review Status: reviewed by expert panel
Collection Method: curation

The c.164T>G (p.Val55Gly) variant has been observed in >10 (113) individuals without a diagnosis of diffuse gastric cancer, signet ring tumor or lobular breast cancer and whose family histories do not suggest HDGC (BS2; SCV000321508.8, SCV000153979.11). In summary, the clinical significance of this variant is classified as likely benign based on BS2 alone, as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): BS2. -

Jul 29, 2024
Department of Pathology and Laboratory Medicine, Sinai Health System
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Breast and/or ovarian cancer Uncertain:1
Apr 25, 2023
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

CDH1-related disorder Uncertain:1
Apr 07, 2023
PreventionGenetics, part of Exact Sciences
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The CDH1 c.164T>G variant is predicted to result in the amino acid substitution p.Val55Gly. This variant has been reported in an individual with colorectal cancer that harbored a pathogenic MUTYH variant (Table A4, Yurgelun et al. 2017. PubMed ID: 28135145). It has been reported in an individual with breast cancer that harbored variants in other genes (Table S2, Wen et al. 2014. PubMed ID: 24969172). It has been reported in an individual with recurrent pregnancy loss (Tables 1 and 2, Quintero-Ronderos et al. 2017. PubMed ID: 29016666). It has been reported in an individual from a healthy, ancestry diverse cohort (Table S1, Bodian et al. PubMed ID: 24728327). The results of RT-PCR analysis suggest this variant does not impact splicing (eTable, Karam et al. 2019. PubMed ID: 31642931). It has also been reported as a somatically-acquired alteration in a pleomorphic xanthoastrocytoma (Table 1, Chan et al. 2017. PubMed ID: 28699883). This variant is reported in 0.0054% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/16-68835573-T-G). It has conflicting interpretation for likely benign and uncertain significance in ClinVar. Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.53
BayesDel_addAF
Uncertain
0.12
D
BayesDel_noAF
Uncertain
0.090
CADD
Pathogenic
30
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.45
T;T;T;.;.
Eigen
Pathogenic
0.76
Eigen_PC
Pathogenic
0.72
FATHMM_MKL
Pathogenic
0.97
D
LIST_S2
Benign
0.64
T;T;T;T;T
M_CAP
Pathogenic
0.40
D
MetaRNN
Uncertain
0.73
D;D;D;D;D
MetaSVM
Uncertain
-0.099
T
MutationAssessor
Pathogenic
3.0
M;.;.;.;M
PrimateAI
Uncertain
0.52
T
PROVEAN
Pathogenic
-4.8
D;.;.;.;D
REVEL
Uncertain
0.64
Sift
Pathogenic
0.0
D;.;.;.;D
Sift4G
Pathogenic
0.0
D;D;D;D;D
Polyphen
1.0
D;.;.;.;.
Vest4
0.63
MVP
0.91
MPC
1.0
ClinPred
0.88
D
GERP RS
5.4
Varity_R
0.97
gMVP
0.86

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Benign
0.50
dbscSNV1_RF
Benign
0.55
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs587778174; hg19: chr16-68835573; COSMIC: COSV55734296; COSMIC: COSV55734296; API