16-68738393-G-C

Variant names:

• chr16-68738393-G-C
• rs1060501223
• NM_004360.5:c.145G>C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 1P and 1B. PM2_Supporting BS2_Supporting

This summary comes from the ClinGen Evidence Repository: The c.145G>C (NM_004360.5) variant in CDH1 is a missense variant predicted to predicted to cause substitution of Gly by Arg at amino acid 49 (p.Gly49Arg). This allele is absent from populations in gnomAD v2.1.1 and v3 (PM2_Supporting). This variant has been observed in ≥3 individuals without GC, DGC, SRC tumours or LBC and whose families do not suggest HDGC (BS2_Supporting). In summary, this variant is classified as uncertain significance for DGLBCS based on the ACMG/AMP criteria applied, as specified by the ClinGen CDH1 VCEP: PM2_Supporting, BS2_Supporting. (CDH1 VCEP specifications version 3.1; 04/24/2023) LINK:https://erepo.genome.network/evrepo/ui/classification/CA396452267/MONDO:0100488/007

• Frequency: Genomes: not found (cov: 32)
• Consequence: CDH1 NM_004360.5 missense
• Clinical Significance: Uncertain significance reviewed by expert panel U:4
• Conservation: PhyloP100: 3.21

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: 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 rank	MANE	Protein	UniProt
CDH1	NM_004360.5	c.145G>C	p.Gly49Arg	missense_variant	Exon 2 of 16	ENST00000261769.10	NP_004351.1
CDH1	NM_001317184.2	c.145G>C	p.Gly49Arg	missense_variant	Exon 2 of 15		NP_001304113.1
CDH1	NM_001317185.2	c.-1471G>C		5_prime_UTR_variant	Exon 2 of 16		NP_001304114.1
CDH1	NM_001317186.2	c.-1675G>C		5_prime_UTR_variant	Exon 2 of 15		NP_001304115.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDH1	ENST00000261769.10	c.145G>C	p.Gly49Arg	missense_variant	Exon 2 of 16	1	NM_004360.5	ENSP00000261769.4
CDH1	ENST00000422392.6	c.145G>C	p.Gly49Arg	missense_variant	Exon 2 of 15	1		ENSP00000414946.2
CDH1	ENST00000566612.5	n.145G>C		non_coding_transcript_exon_variant	Exon 2 of 15	1		ENSP00000454782.1
CDH1	ENST00000566510.5	n.145G>C		non_coding_transcript_exon_variant	Exon 2 of 15	5		ENSP00000458139.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: reviewed by expert panel

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:2

Dec 05, 2023

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces glycine with arginine at codon 49 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 not been identified 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. -

Feb 21, 2017

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.G49R variant (also known as c.145G>C), located in coding exon 2 of the CDH1 gene, results from a G to C substitution at nucleotide position 145. The glycine at codon 49 is replaced by arginine, 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. -

Hereditary diffuse gastric adenocarcinoma Uncertain:1

May 04, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant  is likely to be tolerated. ClinVar contains an entry for this variant (Variation ID: 483261). This variant has not been reported in the literature in individuals affected with CDH1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 49 of the CDH1 protein (p.Gly49Arg). -

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

Aug 02, 2023

ClinGen CDH1 Variant Curation Expert Panel

Significance: Uncertain significance

Review Status: reviewed by expert panel

Collection Method: curation

The c.145G>C (NM_004360.5) variant in CDH1 is a missense variant predicted to predicted to cause substitution of Gly by Arg at amino acid 49 (p.Gly49Arg). This allele is absent from populations in gnomAD v2.1.1 and v3 (PM2_Supporting). This variant has been observed in at least individuals without GC, DGC, SRC tumours or LBC and whose families do not suggest HDGC (BS2_Supporting). In summary, this variant is classified as uncertain significance for DGLBCS based on the ACMG/AMP criteria applied, as specified by the ClinGen CDH1 VCEP: PM2_Supporting, BS2_Supporting. (CDH1 VCEP specifications version 3.1; 04/24/2023) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.52
BayesDel_addAF	Benign	0.011	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.40	T;T;T;.;.
Eigen	Benign	-0.17
Eigen_PC	Benign	-0.15
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.79	T;T;T;T;T
M_CAP	Uncertain	0.093	D
MetaRNN	Pathogenic	0.79	D;D;D;D;D
MetaSVM	Benign	-0.51	T
MutationAssessor	Uncertain	2.9	M;.;.;.;M
PrimateAI	Uncertain	0.60	T
PROVEAN	Uncertain	-3.0	D;.;.;.;D
REVEL	Uncertain	0.31
Sift	Uncertain	0.0020	D;.;.;.;D
Sift4G	Benign	0.062	T;D;T;D;T
Polyphen		0.48	P;.;.;.;.
Vest4		0.62
MutPred		0.84		Gain of sheet (P = 0.0266);Gain of sheet (P = 0.0266);Gain of sheet (P = 0.0266);Gain of sheet (P = 0.0266);Gain of sheet (P = 0.0266);
MVP		0.81
MPC		0.36
ClinPred		0.97	D
GERP RS		2.8
Varity_R		0.33
gMVP		0.67

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: rs1060501223; hg19: chr16-68772296;