16-68801774-C-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM1BP4BS2

The ENST00000261769.10(CDH1):​c.268C>T​(p.Arg90Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000198 in 1,461,806 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R90Q) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.000020 ( 0 hom. )

Consequence

CDH1
ENST00000261769.10 missense

Scores

1
18

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6B:1

Conservation

PhyloP100: 0.816
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PM1
In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 4 benign, 15 uncertain in ENST00000261769.10
BP4
Computational evidence support a benign effect (MetaRNN=0.2782811).
BS2
High AC in GnomAdExome4 at 29 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
CDH1NM_004360.5 linkuse as main transcriptc.268C>T p.Arg90Trp missense_variant 3/16 ENST00000261769.10 NP_004351.1
CDH1NM_001317184.2 linkuse as main transcriptc.268C>T p.Arg90Trp missense_variant 3/15 NP_001304113.1
CDH1NM_001317185.2 linkuse as main transcriptc.-1348C>T 5_prime_UTR_variant 3/16 NP_001304114.1
CDH1NM_001317186.2 linkuse as main transcriptc.-1552C>T 5_prime_UTR_variant 3/15 NP_001304115.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
CDH1ENST00000261769.10 linkuse as main transcriptc.268C>T p.Arg90Trp missense_variant 3/161 NM_004360.5 ENSP00000261769 P1P12830-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.00000398
AC:
1
AN:
251338
Hom.:
0
AF XY:
0.00000736
AC XY:
1
AN XY:
135838
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0000544
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000198
AC:
29
AN:
1461806
Hom.:
0
Cov.:
32
AF XY:
0.0000206
AC XY:
15
AN XY:
727202
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000224
Gnomad4 ASJ exome
AF:
0.0000383
Gnomad4 EAS exome
AF:
0.000101
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000198
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
Cov.:
32
Alfa
AF:
0.0000712
Hom.:
0
Bravo
AF:
0.0000227
EpiCase
AF:
0.0000545
EpiControl
AF:
0.00

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:6Benign:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Hereditary diffuse gastric adenocarcinoma Uncertain:3
Uncertain significance, criteria provided, single submitterclinical testingMyriad Genetics, Inc.Mar 06, 2023This 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. -
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 18, 2024This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 90 of the CDH1 protein (p.Arg90Trp). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with gastric cancer (PMID: 23555086). ClinVar contains an entry for this variant (Variation ID: 182390). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitterclinical testingCounsylNov 08, 2016- -
Hereditary cancer-predisposing syndrome Uncertain:1Benign:1
Likely benign, criteria provided, single submitterclinical testingAmbry GeneticsJun 06, 2023This 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. -
Uncertain significance, criteria provided, single submitterclinical testingColor Diagnostics, LLC DBA Color HealthOct 09, 2023This missense variant replaces arginine with tryptophan at codon 90 of the CDH1 protein. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in one individual affected with familial gastric cancer in the literature (PMID: 23555086). In a large breast cancer case-control study, this variant was identified in 4/60466 cases and 1/53461 unaffected controls (PMID: 33471991). This variant has been identified in 1/251338 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingGeneDxOct 21, 2021Not observed at significant frequency in large population cohorts (Lek 2016); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in an individual with a personal and family history of gastric cancer (Fang 2013); This variant is associated with the following publications: (PMID: 24983367, 25925381, 23555086) -
Familial cancer of breast Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingBaylor GeneticsDec 29, 2023- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.10
BayesDel_addAF
Benign
-0.082
T
BayesDel_noAF
Benign
-0.36
CADD
Benign
19
DANN
Benign
0.64
DEOGEN2
Benign
0.37
T;T;T;.;.
Eigen
Benign
-0.75
Eigen_PC
Benign
-0.77
FATHMM_MKL
Benign
0.14
N
LIST_S2
Benign
0.69
T;D;T;D;D
M_CAP
Benign
0.060
D
MetaRNN
Benign
0.28
T;T;T;T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
0.34
N;.;.;.;N
MutationTaster
Benign
1.0
N;N
PrimateAI
Benign
0.21
T
PROVEAN
Benign
-1.9
N;.;.;.;N
REVEL
Benign
0.15
Sift
Benign
0.039
D;.;.;.;D
Sift4G
Uncertain
0.053
T;D;T;D;T
Polyphen
0.0010
B;.;.;.;.
Vest4
0.19
MutPred
0.69
Loss of catalytic residue at R90 (P = 0.0363);Loss of catalytic residue at R90 (P = 0.0363);Loss of catalytic residue at R90 (P = 0.0363);Loss of catalytic residue at R90 (P = 0.0363);Loss of catalytic residue at R90 (P = 0.0363);
MVP
0.78
MPC
0.66
ClinPred
0.26
T
GERP RS
2.2
Varity_R
0.11
gMVP
0.33

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.090
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: rs730881661; hg19: chr16-68835677; COSMIC: COSV55745537; API