16-68813398-C-T

Position:

• chr16-68813398-C-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BS1 BS2

This summary comes from the ClinGen Evidence Repository: The c.1223C>T (p.Ala408Val) missense variant has a frequency of 0.114% (>0.1%) in South Asians (35 of 30616 alleles) in the gnomAD v2.1.1 cohort (BS1). This variant has been observed in ≥10 (122) individuals without DGC, SRC tumours or LBC and whose families do not suggest HDGC (BS2; SCV000260430.7, SCV000186167.6). In summary, the clinical significance of this variant is classified as of benign based the ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): BS1, BS2. LINK:https://erepo.genome.network/evrepo/ui/classification/CA288022/MONDO:0007648/007

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000088 (1 hom.)
• Consequence: CDH1 NM_004360.5 missense
• Clinical Significance: Benign reviewed by expert panel U:4 B:11 O:1
• Conservation: PhyloP100: 2.73

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BS1: 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	UniProt
CDH1	NM_004360.5	c.1223C>T	p.Ala408Val	missense_variant	9/16	ENST00000261769.10	NP_004351.1
CDH1	NM_001317185.2	c.-393C>T		5_prime_UTR_variant	9/16		NP_001304114.1
CDH1	NM_001317186.2	c.-597C>T		5_prime_UTR_variant	9/15		NP_001304115.1
CDH1	NM_001317184.2	c.1137+1135C>T		intron_variant			NP_001304113.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDH1	ENST00000261769.10	c.1223C>T	p.Ala408Val	missense_variant	9/16	1	NM_004360.5	ENSP00000261769.4

Frequencies

GnomAD3 genomes AF: 0.000118 AC: 18 AN: 152098 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000362

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000179 AC: 45 AN: 251484 Hom.: 0 AF XY: 0.000287 AC XY: 39 AN XY: 135916

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00114

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000527

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000876 AC: 128 AN: 1461820 Hom.: 1 Cov.: 32 AF XY: 0.000133 AC XY: 97 AN XY: 727212

Gnomad4 AFR exome AF: 0.000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000202

Gnomad4 SAS exome AF: 0.000974

Gnomad4 FIN exome AF: 0.0000374

Gnomad4 NFE exome AF: 0.0000153

Gnomad4 OTH exome AF: 0.000116

GnomAD4 genome AF: 0.000118 AC: 18 AN: 152098 Hom.: 0 Cov.: 32 AF XY: 0.0000808 AC XY: 6 AN XY: 74282

Gnomad4 AFR AF: 0.000362

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000622

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000125 Hom.: 0

Bravo AF: 0.0000945

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000189 AC: 23

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

Significance: Benign

Submissions summary: Uncertain:4 Benign:11 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Hereditary diffuse gastric adenocarcinoma Uncertain:2 Benign:3 Other:1

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Mar 07, 2023	This variant is considered likely benign. Homozygosity has been confirmed in one or more individuals. As homozygosity for pathogenic variants in this gene is generally assumed to result in embryonic lethality, this variant is unlikely to be pathogenic. -
not provided, no classification provided	phenotyping only	GenomeConnect - Invitae Patient Insights Network	-	Variant interpreted as Uncertain significance and reported on 01-24-2018 by Lab Myriad. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. -
Benign, criteria provided, single submitter	clinical testing	Mendelics	Aug 22, 2023	- -
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	Not applicable criteria (PMID: 30311375) -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Jan 06, 2016	- -

Hereditary cancer-predisposing syndrome Uncertain:1 Benign:3

Likely benign, criteria provided, single submitter	curation	Sema4, Sema4	Mar 09, 2022	- -
Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Feb 12, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Dec 22, 2021	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. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneKor MSA	Aug 01, 2018	- -

not specified Uncertain:1 Benign:2

Uncertain significance, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	-	- -
Benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Feb 06, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 28, 2019	Variant summary: CDH1 c.1223C>T (p.Ala408Val) results in a non-conservative amino acid change located in a cadherin repeat (IPR002126) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00015 in 324684 control chromosomes (gnomAD and publication data), predominantly at a frequency of 0.0011 within the South Asian subpopulation in the gnomAD database. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 40-folds higher than the estimated maximal expected allele frequency for a pathogenic variant in CDH1 causing Hereditary Diffuse Gastric Cancer phenotype (2.8e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of South Asian origin. Though the variant, c.1223C>T, has been reported in the literature in individuals affected with Hereditary Diffuse Gastric Cancer, colorectal cancer, and breast cancer (Caminsky_2016, Luber_2011, Mannan_2016, Mu_2016, Ross_2013, Schrader_2010, Tung_2015, Yurgeuln_2015, Momozawa_2018), it was also found in healthy controls (Momozawa_2018). 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. Eight ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant, six times as uncertain significance, and twice as likely benign. Based on the evidence outlined above, the variant was classified as likely benign. -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	May 09, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 02, 2020	This variant is associated with the following publications: (PMID: 22152101, 26759166, 23575477, 20921021, 25980754, 26674224, 26182300, 26898890, 26911350, 25186627, 29470806, 30287823, 31159747) -

CDH1-related diffuse gastric and lobular breast cancer syndrome Benign:1

Benign, reviewed by expert panel

curation

ClinGen CDH1 Variant Curation Expert Panel

Aug 10, 2023

The c.1223C>T (p.Ala408Val) missense variant has a frequency of 0.114% (>0.1%) in South Asians (35 of 30616 alleles) in the gnomAD v2.1.1 cohort (BS1). This variant has been observed in at least 10 (122) individuals without DGC, SRC tumours or LBC and whose families do not suggest HDGC (BS2; SCV000260430.7, SCV000186167.6). In summary, the clinical significance of this variant is classified as of benign based the ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): BS1, BS2. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.50
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.24
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.50	D;T;T;.
Eigen	Uncertain	0.35
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.95	D;D;D;D
M_CAP	Benign	0.026	D
MetaRNN	Benign	0.21	T;T;T;T
MetaSVM	Benign	-0.65	T
MutationAssessor	Pathogenic	3.3	M;.;.;.
PrimateAI	Benign	0.42	T
PROVEAN	Uncertain	-3.4	D;.;.;.
REVEL	Uncertain	0.35
Sift	Uncertain	0.0090	D;.;.;.
Sift4G	Benign	0.078	T;D;T;D
Polyphen		1.0	D;.;.;.
Vest4		0.59
MVP		0.88
MPC		0.88
ClinPred		0.26	T
GERP RS		5.1
Varity_R		0.26
gMVP		0.63

Splicing

Name	Calibrated prediction	Score	Prediction
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

Other links and lift over

dbSNP: rs138135866; hg19: chr16-68847301; COSMIC: COSV55733660; COSMIC: COSV55733660;