rs201141645

Positions:

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BS1BS2

This summary comes from the ClinGen Evidence Repository: The c.546A>C (p.Lys182Asn) variant has an allele frequency of 0.00104 (>0.1%, 9 out of 8628 alleles) in the East Asian subpopulation of the ExAC cohort (BS1). The variant has also been observed in >10 (56) individuals without a diagnosis of diffuse gastric cancer, signet ring tumor or lobular breast cancer and whose family histories do not suggest HDGC (BS2; SCV000637839.5; SCV000566004.5). Therefore, this variant meets criteria to be classified as benign. 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/CA163740/MONDO:0007648/007

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000033 ( 0 hom. )

Consequence

CDH1
NM_004360.5 missense

Scores

Clinical Significance

Benign reviewed by expert panel U:3B:6

Conservation

PhyloP100: 0.242

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 Benign. Variant got -8 ACMG points.

BS1

BS2

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
CDH1	NM_004360.5 linkuse as main transcript	c.546A>C	p.Lys182Asn	missense_variant	5/16	ENST00000261769.10
CDH1	NM_001317184.2 linkuse as main transcript	c.546A>C	p.Lys182Asn	missense_variant	5/15
CDH1	NM_001317185.2 linkuse as main transcript	c.-1070A>C		5_prime_UTR_variant	5/16
CDH1	NM_001317186.2 linkuse as main transcript	c.-1274A>C		5_prime_UTR_variant	5/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDH1	ENST00000261769.10 linkuse as main transcript	c.546A>C	p.Lys182Asn	missense_variant	5/16	1	NM_004360.5	P1	P12830-1

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152216

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:

0.000577

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:

0.0000796

AC:

AN:

251196

Hom.:

AF XY:

0.000110

AC XY:

AN XY:

135770

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000815

Gnomad SAS exome

AF:

0.000131

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000881

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000328

AC:

AN:

1461866

Hom.:

Cov.:

AF XY:

0.0000426

AC XY:

AN XY:

727234

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000831

Gnomad4 SAS exome

AF:

0.0000580

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000629

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152334

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74486

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000578

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000104

Hom.:

Bravo

AF:

0.0000340

ExAC

AF:

0.000115

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Benign

Submissions summary: Uncertain:3Benign:6

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome

Uncertain:2Benign:2

Uncertain significance, criteria provided, single submitter	curation	Sema4, Sema4	Aug 04, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 25, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneKor MSA	Aug 01, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 05, 2021	This alteration is classified as 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. -

Malignant tumor of breast

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

The CDH1 p.Lys182Asn variant was not reported in the literature as identified in an affected population. The variant was identified in dbSNP (ID: rs201141645 as "With Likely benign, Uncertain significance allele") and ClinVar (3x as uncertain significance by Ambry Genetics, GeneDx, and Invitae). The variant was not identified in Cosmic, MutDB, or Zhejiang University databases. The variant was identified in control databases in 21 of 276982 chromosomes at a frequency of 0.00007 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: East Asian in 15 of 18866 chromosomes (freq: 0.0008), Other in 1 of 6466 chromosomes (freq: 0.0002), European in 1 of 126514 chromosomes (freq: 0.000008), and South Asian in 4 of 30780 chromosomes (freq: 0.0001), while the variant was not observed in the African, Latino, Ashkenazi Jewish, or Finnish populations. One aggregation assay showed that the Lys182Asn variant behaved similarly to the wildtype protein in CHO cells (Cho 2017). The p.Lys182 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and only 1 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

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

Feb 03, 2022

Variant summary: CDH1 c.546A>C (p.Lys182Asn) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 8e-05 in 251196 control chromosomes, predominantly at a frequency of 0.00082 within the East Asian subpopulation in the gnomAD database. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 39 fold of the estimated maximal expected allele frequency for a pathogenic variant in CDH1 causing Breast Cancer phenotype (2.1e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. To our knowledge, no occurrence of c.546A>C in individuals affected with Breast Cancer and no experimental evidence demonstrating its impact on protein function have been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (Benign n=2, likely benign n=2, VUS n=2). Based on the evidence outlined above, the variant was classified as benign. -

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Jan 19, 2021

Observed in individuals with diffuse gastric cancer (Cho 2017); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Observed in 0.008% (20/251196 alleles) in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 28522256, 31159747, 32426482, 33309985, 32241597) -

Hereditary diffuse gastric adenocarcinoma

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2024

- -

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.546A>C (p.Lys182Asn) variant has an allele frequency of 0.00104 (>0.1%, 9 out of 8628 alleles) in the East Asian subpopulation of the ExAC cohort (BS1). The variant has also been observed in >10 (56) individuals without a diagnosis of diffuse gastric cancer, signet ring tumor or lobular breast cancer and whose family histories do not suggest HDGC (BS2; SCV000637839.5; SCV000566004.5). Therefore, this variant meets criteria to be classified as benign. 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

Pathogenic

0.60

BayesDel_addAF

Benign

-0.50

BayesDel_noAF

Benign

-0.57

CADD

Benign

DANN

Benign

0.95

DEOGEN2

Uncertain

0.44

T;T;T;.;.

Eigen

Benign

-0.34

Eigen_PC

Benign

-0.22

FATHMM_MKL

Benign

0.71

LIST_S2

Uncertain

0.86

D;T;T;T;T

M_CAP

Benign

0.013

MetaRNN

Benign

0.035

T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.3

M;.;.;.;M

MutationTaster

Benign

0.82

N;N

PrimateAI

Benign

0.32

PROVEAN

Uncertain

-2.5

N;.;.;.;D

REVEL

Benign

0.031

Sift

Benign

0.080

T;.;.;.;T

Sift4G

Benign

0.21

T;T;T;T;T

Polyphen

0.51

P;.;.;.;.

Vest4

0.13

MutPred

0.38

Gain of ubiquitination at K179 (P = 0.0222);Gain of ubiquitination at K179 (P = 0.0222);Gain of ubiquitination at K179 (P = 0.0222);Gain of ubiquitination at K179 (P = 0.0222);Gain of ubiquitination at K179 (P = 0.0222);

MVP

0.73

MPC

0.50

ClinPred

0.051

GERP RS

2.3

Varity_R

0.49

gMVP

0.29

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

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