rs587778172

Positions:

chr16-68801828-A-G

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_004360.5(CDH1):c.322A>G(p.Arg108Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000991 in 1,614,108 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. R108R) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000096 ( 0 hom. )

Consequence

CDH1
NM_004360.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:5O:1

Conservation

PhyloP100: 2.21

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:

CDH1 (HGNC:):

CDH1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.18205345).

BS2

High AC in GnomAdExome4 at 14 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CDH1	NM_004360.5 linkuse as main transcript	c.322A>G	p.Arg108Gly	missense_variant	3/16	ENST00000261769.10	NP_004351.1	P12830-1A0A0U2ZQU7B3GN61
CDH1	NM_001317184.2 linkuse as main transcript	c.322A>G	p.Arg108Gly	missense_variant	3/15		NP_001304113.1	P12830-2B3GN61
CDH1	NM_001317185.2 linkuse as main transcript	c.-1294A>G		5_prime_UTR_variant	3/16		NP_001304114.1	P12830B3GN61Q9UII7
CDH1	NM_001317186.2 linkuse as main transcript	c.-1498A>G		5_prime_UTR_variant	3/15		NP_001304115.1	P12830B3GN61

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDH1	ENST00000261769.10 linkuse as main transcript	c.322A>G	p.Arg108Gly	missense_variant	3/16	1	NM_004360.5	ENSP00000261769.4		P12830-1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152226

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000199

AC:

AN:

251244

Hom.:

AF XY:

0.0000147

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:

0.00

Gnomad SAS exome

AF:

0.000163

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000958

AC:

AN:

1461882

Hom.:

Cov.:

AF XY:

0.0000110

AC XY:

AN XY:

727244

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000162

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152226

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74366

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000655

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ExAC

AF:

0.0000247

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5Other:1

Revision: criteria provided, multiple submitters, no conflicts

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	Apr 04, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Mar 03, 2023	The p.R108G variant (also known as c.322A>G), located in coding exon 3 of the CDH1 gene, results from an A to G substitution at nucleotide position 322. The arginine at codon 108 is replaced by glycine, an amino acid with dissimilar 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. -

Familial cancer of breast;C0476089:Endometrial carcinoma;C1140680:Ovarian cancer;C1708349:Hereditary diffuse gastric adenocarcinoma;C4551988:Blepharocheilodontic syndrome 1

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jun 19, 2024

- -

Hereditary diffuse gastric adenocarcinoma

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 23, 2022

This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 108 of the CDH1 protein (p.Arg108Gly). This variant is present in population databases (rs587778172, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with CDH1-related conditions. ClinVar contains an entry for this variant (Variation ID: 133851). 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. 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. -

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.Arg108Gly variant was identified in a study of 158 genes causally implicated in carcinogenesis in healthy individuals and was found in 1 of 1362 control chromosomes (freq. 0.001) (Bodian 2014). The variant was also identified in dbSBP (ID: rs587778172) as â€šÃ„ÃºWith untested allele,â€šÃ„Ã¹ ClinVar (not classified), and Clinvitae databases. The variant was not identified in Cosmic, MutDB, Insight Colon Cancer Gene Variant Database, Zhejiang Colon Cancer Database. The variant was identified in control databases in 5 of 245988 chromosomes at a frequency of 0.00002 increasing the likelihood that this may be a low frequency benign variant in certain populations of origin (Genome Aggregation Consortium Feb 27, 2017). The variant was only found in the South Asian population in 5 of 30780 chromosomes (freq. 0.00016). The p.Arg108Gly residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. The variant is located with the Cadherin prodomain Cadherin-like functional domain(s) increasing the likelihood that it may have clinical significance. 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

Other:1

not provided, no classification provided

reference population

ITMI

Sep 19, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Benign

-0.28

CADD

Benign

DANN

Benign

0.87

DEOGEN2

Benign

0.28

T;T;T;.;.

Eigen

Benign

-0.44

Eigen_PC

Benign

-0.48

FATHMM_MKL

Benign

0.50

LIST_S2

Benign

0.85

T;D;T;D;T

M_CAP

Benign

0.027

MetaRNN

Benign

0.18

T;T;T;T;T

MetaSVM

Benign

-0.98

MutationAssessor

Uncertain

2.4

M;.;.;.;M

PrimateAI

Benign

0.32

PROVEAN

Benign

-2.2

N;.;.;.;N

REVEL

Benign

0.24

Sift

Benign

0.12

T;.;.;.;T

Sift4G

Benign

0.20

T;T;T;T;T

Polyphen

0.67

P;.;.;.;.

Vest4

0.50

MutPred

0.65

Loss of MoRF binding (P = 0.0088);Loss of MoRF binding (P = 0.0088);Loss of MoRF binding (P = 0.0088);Loss of MoRF binding (P = 0.0088);Loss of MoRF binding (P = 0.0088);

MVP

0.79

MPC

0.36

ClinPred

0.10

GERP RS

1.7

Varity_R

0.29

gMVP

0.38

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