16-68815759-C-T

Position:

chr16-68815759-C-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BS2BP2_Strong

This summary comes from the ClinGen Evidence Repository: The NM_004360.5(CDH1): c.1565C>T (p.Thr522Ile) variant has been observed in >10 individuals without a diagnosis of diffuse gastric cancer, signet ring tumor or lobular breast cancer and whose family histories do not suggest HDGC (BS2; internal laboratory contributors). This variant was observed in the homozygous state in 1 individual without personal and/or family history of DGC, LBC, or SRC tumors (BP2_strong; internal laboratory contributors). This variant is known in one family with HDGC criteria (ERN_GENTURIS). In summary, the clinical significance of this variant is classified as benign based on BS2 and BP2_strong. ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel: BS2, BP2_strong. (CDH1 VCEP specifications version 3.1; 06/26/2023) LINK:https://erepo.genome.network/evrepo/ui/classification/CA337526/MONDO:0100488/007

Frequency

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

Exomes 𝑓: 0.0000075 ( 0 hom. )

Consequence

CDH1
ENST00000261769.10 missense, splice_region

Scores

Splicing: ADA: 0.1037

Clinical Significance

Benign reviewed by expert panel U:6B:3

Conservation

PhyloP100: 0.463

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:

(HGNC:):

links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP2

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

BS2

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
CDH1	NM_004360.5 linkuse as main transcript	c.1565C>T	p.Thr522Ile	missense_variant, splice_region_variant	10/16	ENST00000261769.10	NP_004351.1
CDH1	NM_001317184.2 linkuse as main transcript	c.1382C>T	p.Thr461Ile	missense_variant, splice_region_variant	9/15		NP_001304113.1
CDH1	NM_001317185.2 linkuse as main transcript	c.17C>T	p.Thr6Ile	missense_variant, splice_region_variant	10/16		NP_001304114.1
CDH1	NM_001317186.2 linkuse as main transcript	c.-255C>T		splice_region_variant, 5_prime_UTR_variant	10/15		NP_001304115.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDH1	ENST00000261769.10 linkuse as main transcript	c.1565C>T	p.Thr522Ile	missense_variant, splice_region_variant	10/16	1	NM_004360.5	ENSP00000261769	P1	P12830-1
	ENST00000563916.1 linkuse as main transcript	n.264-100G>A		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152188

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000192

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:

0.00000796

AC:

AN:

251328

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135850

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:

0.00000880

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000752

AC:

AN:

1461854

Hom.:

Cov.:

AF XY:

0.00000825

AC XY:

AN XY:

727226

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000450

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152188

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74332

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000192

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Benign

Submissions summary: Uncertain:6Benign:3

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Hereditary diffuse gastric adenocarcinoma

Uncertain:3Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Mar 03, 2023	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. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	European Reference Network on Genetic Tumour Risk Syndromes (ERN-GENTURIS), i3s - Instituto de Investigação e Inovação em Saúde, University of Porto	Aug 01, 2022	PS4_Supporting; PM2 (PMID: 30311375) -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Mar 17, 2016	- -

Hereditary cancer-predisposing syndrome

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Mar 08, 2023	The p.T522I variant (also known as c.1565C>T), located in coding exon 10 of the CDH1 gene, results from a C to T substitution at nucleotide position 1565. The amino acid change results in threonine to isoleucine at codon 522, an amino acid with similar properties. This alteration was observed in with an allele frequency of 0.00009 in 11241 female controls and was not observed in 7051 unselected female breast cancer patients of Japanese ancestry (Momozawa Y et al. Nat Commun, 2018 10;9:4083). This alteration was also identified in 1/1358 non-cancer control individuals and in 0/57 cases, in a study looking at cancer predisposition mutations in patients with cutaneous melanoma and a history of at least two additional non-cutaneous melanoma primary cancers (Pritchard AL et al. PLoS One, 2018 Apr;13:e0194098). 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Dec 30, 2019	This missense variant replaces threonine with isoleucine at codon 522 of the CDH1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 2/251328 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 specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Mar 14, 2023

Variant summary: CDH1 c.1565C>T (p.Thr522Ile) results in a non-conservative amino acid change located in the Cadherin-like domain of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 1.4e-05 in 276562 control chromosomes (gnomAD and publications). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1565C>T has been reported in the literature in an individual affected with nonsyndromic oral clefts (Ittiwu_2016) and an individual affected with ichthyosis vulgaris and atopic dermatitis (Taylan_2015). 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. Five ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (n=3) or likely benign/benign (n=2). Based on the evidence outlined above, the variant was classified as uncertain significance. -

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

May 12, 2021

In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Observed in individuals with oral clefts, ichthyosis vulgaris or atopic dermatitis (Taylan 2015, Ittiwat 2016); This variant is associated with the following publications: (PMID: 31638429, 30287823, 19593635, 25819062, 27227907, 29641532) -

CDH1-related diffuse gastric and lobular breast cancer syndrome

Benign:1

Benign, reviewed by expert panel

curation

ClinGen CDH1 Variant Curation Expert Panel

Aug 03, 2023

The NM_004360.5(CDH1): c.1565C>T (p.Thr522Ile) variant has been observed in >10 individuals without a diagnosis of diffuse gastric cancer, signet ring tumor or lobular breast cancer and whose family histories do not suggest HDGC (BS2; internal laboratory contributors). This variant was observed in the homozygous state in 1 individual without personal and/or family history of DGC, LBC, or SRC tumors (BP2_strong; internal laboratory contributors). This variant is known in one family with HDGC criteria (ERN_GENTURIS). In summary, the clinical significance of this variant is classified as benign based on BS2 and BP2_strong. ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel: BS2, BP2_strong. (CDH1 VCEP specifications version 3.1; 06/26/2023) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.16

BayesDel_noAF

Benign

-0.30

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.49

T;T;T;.;.

Eigen

Uncertain

0.48

Eigen_PC

Uncertain

0.46

FATHMM_MKL

Uncertain

0.86

LIST_S2

Benign

0.84

T;T;T;T;T

M_CAP

Benign

0.010

MetaRNN

Uncertain

0.68

D;D;D;D;D

MetaSVM

Benign

-0.70

MutationAssessor

Uncertain

2.2

M;.;.;.;.

MutationTaster

Benign

1.0

D;D

PrimateAI

Benign

0.40

PROVEAN

Uncertain

-3.4

D;.;.;.;D

REVEL

Uncertain

0.31

Sift

Benign

0.097

T;.;.;.;D

Sift4G

Benign

0.072

T;T;T;T;T

Polyphen

0.98

D;.;.;.;.

Vest4

0.75

MutPred

0.60

Gain of methylation at K520 (P = 0.0461);Gain of methylation at K520 (P = 0.0461);.;Gain of methylation at K520 (P = 0.0461);.;

MVP

0.92

MPC

0.49

ClinPred

0.89

GERP RS

4.8

Varity_R

0.11

gMVP

0.42

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.10

dbscSNV1_RF

Benign

0.22

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.

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