rs587778171

chr16-68738361-C-Achr16-68738361-C-Gchr16-68738361-C-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 2P and 8B. PM1BP6_Very_Strong

The NM_004360.5(CDH1):c.113C>A(p.Thr38Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000838 in 1,551,090 control chromosomes in the GnomAD database, with no homozygous occurrence. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T38M) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000086 ( 0 hom. )

Consequence

CDH1
NM_004360.5 missense

Scores

Clinical Significance

Likely benign reviewed by expert panel U:3B:1

Conservation

PhyloP100: 0.288

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]

CDH1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 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 NM_004360.5

BP6

Variant 16-68738361-C-A is Benign according to our data. Variant chr16-68738361-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 231383.Status of the report is reviewed_by_expert_panel, 3 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
CDH1	NM_004360.5 linkuse as main transcript	c.113C>A	p.Thr38Lys	missense_variant	2/16	ENST00000261769.10
CDH1	NM_001317184.2 linkuse as main transcript	c.113C>A	p.Thr38Lys	missense_variant	2/15
CDH1	NM_001317185.2 linkuse as main transcript	c.-1503C>A		5_prime_UTR_variant	2/16
CDH1	NM_001317186.2 linkuse as main transcript	c.-1707C>A		5_prime_UTR_variant	2/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDH1	ENST00000261769.10 linkuse as main transcript	c.113C>A	p.Thr38Lys	missense_variant	2/16	1	NM_004360.5	P1	P12830-1
CDH1	ENST00000422392.6 linkuse as main transcript	c.113C>A	p.Thr38Lys	missense_variant	2/15	1			P12830-2
CDH1	ENST00000566612.5 linkuse as main transcript	c.113C>A	p.Thr38Lys	missense_variant, NMD_transcript_variant	2/15	1
CDH1	ENST00000566510.5 linkuse as main transcript	c.113C>A	p.Thr38Lys	missense_variant, NMD_transcript_variant	2/15	5

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152224

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000191

AC:

AN:

156704

Hom.:

AF XY:

0.0000242

AC XY:

AN XY:

82632

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000406

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000879

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000858

AC:

AN:

1398866

Hom.:

Cov.:

AF XY:

0.00000870

AC XY:

AN XY:

689938

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000280

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000126

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000172

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152224

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74380

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ExAC

AF:

0.0000243

AC:

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:3Benign:1

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Feb 16, 2023	This missense variant replaces threonine with lysine at codon 38 of the CDH1 protein. To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with CDH1-related disorders in the literature. This variant has been identified in 3/156704 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Mar 27, 2023	The p.T38K variant (also known as c.113C>A), located in coding exon 2 of the CDH1 gene, results from a C to A substitution at nucleotide position 113. The threonine at codon 38 is replaced by lysine, an amino acid with similar properties. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Hereditary diffuse gastric adenocarcinoma

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Nov 27, 2022

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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 231383). This variant has not been reported in the literature in individuals affected with CDH1-related conditions. This variant is present in population databases (rs587778171, gnomAD 0.009%). This sequence change replaces threonine, which is neutral and polar, with lysine, which is basic and polar, at codon 38 of the CDH1 protein (p.Thr38Lys). -

CDH1-related diffuse gastric and lobular breast cancer syndrome

Benign:1

Likely benign, reviewed by expert panel

curation

ClinGen CDH1 Variant Curation Expert Panel

Aug 17, 2023

The c.113C>A (p.Thr38Lys) variant results in a non-synonymous amino acid substitution in exon 2 of CDH1. This variant has been observed in at least 10 individuals without DGC, LBC or SRC tumors and whose families do not suggest HDGC (BS2; SCV000637699.3, SCV000275215.5). In summary, this variant meets criteria to be classified as likely benign based the ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): BS2. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.37

Cadd

Benign

Dann

Benign

0.96

DEOGEN2

Benign

0.27

T;T;T;.;.

Eigen

Benign

0.019

Eigen_PC

Benign

-0.088

FATHMM_MKL

Benign

0.52

LIST_S2

Benign

0.79

T;T;T;T;T

M_CAP

Benign

0.028

MetaRNN

Uncertain

0.60

D;D;D;D;D

MetaSVM

Benign

-0.95

MutationAssessor

Benign

1.9

M;.;.;.;M

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.48

PROVEAN

Benign

-2.3

N;.;.;.;N

REVEL

Benign

0.22

Sift

Uncertain

0.0080

D;.;.;.;D

Sift4G

Benign

0.066

T;D;T;D;T

Polyphen

0.90

P;.;.;.;.

Vest4

0.68

MutPred

0.64

Gain of ubiquitination at T38 (P = 0.0238);Gain of ubiquitination at T38 (P = 0.0238);Gain of ubiquitination at T38 (P = 0.0238);Gain of ubiquitination at T38 (P = 0.0238);Gain of ubiquitination at T38 (P = 0.0238);

MVP

0.83

MPC

0.44

ClinPred

0.31

GERP RS

1.6

Varity_R

0.34

gMVP

0.47

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over