chr16-68738360-A-C

Variant names:

• chr16-68738360-A-C
• rs786203442
• NM_004360.5:c.112A>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.112A>C (NM_004360.5) variant in CDH1 is a missense variant predicted to cause substitution in exon 2 (p.Thr38Pro). This variant was observed in seven individuals with no DGC, LBC or SRC tumours and whose families do not suggest HDGC (BS2_Supporting; Invitae). Note that this includes two individuals with a family history of stomach cancer NOS. This variant is absent from gnomAD 2.1.1 (PM2_Spporting). 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/CA396452065/MONDO:0100488/007

• Frequency: Genomes: not found (cov: 32)
• Consequence: CDH1 NM_004360.5 missense
• Clinical Significance: Uncertain significance reviewed by expert panel U:5
• Conservation: PhyloP100: 1.41

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.112A>C	p.Thr38Pro	missense_variant	Exon 2 of 16	ENST00000261769.10	NP_004351.1
CDH1	NM_001317184.2	c.112A>C	p.Thr38Pro	missense_variant	Exon 2 of 15		NP_001304113.1
CDH1	NM_001317185.2	c.-1504A>C		5_prime_UTR_variant	Exon 2 of 16		NP_001304114.1
CDH1	NM_001317186.2	c.-1708A>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.112A>C	p.Thr38Pro	missense_variant	Exon 2 of 16	1	NM_004360.5	ENSP00000261769.4
CDH1	ENST00000422392.6	c.112A>C	p.Thr38Pro	missense_variant	Exon 2 of 15	1		ENSP00000414946.2
CDH1	ENST00000566612.5	n.112A>C		non_coding_transcript_exon_variant	Exon 2 of 15	1		ENSP00000454782.1
CDH1	ENST00000566510.5	n.112A>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:5

Revision: reviewed by expert panel

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:2

Mar 06, 2024

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces threonine with proline at codon 38 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 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. -

Dec 04, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.T38P variant (also known as c.112A>C), located in coding exon 2 of the CDH1 gene, results from an A to C substitution at nucleotide position 112. The threonine at codon 38 is replaced by proline, an amino acid with highly similar 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

Nov 16, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces threonine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 38 of the CDH1 protein (p.Thr38Pro). This variant is not present in population databases (gnomAD no frequency). 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: 489846). 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. 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. -

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.112A>C (NM_004360.5) variant in CDH1 is a missense variant predicted to cause substitution in exon 2 (p.Thr38Pro). This variant was observed in seven individuals with no DGC, LBC or SRC tumours and whose families do not suggest HDGC (BS2_Supporting; Invitae). Note that this includes two individuals with a family history of stomach cancer NOS. This variant is absent from gnomAD 2.1.1 (PM2_Spporting). 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) -

Familial cancer of breast Uncertain:1

Sep 06, 2023

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.015	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.34	T;T;T;.;.
Eigen	Benign	0.17
Eigen_PC	Benign	0.056
FATHMM_MKL	Benign	0.62	D
LIST_S2	Benign	0.70	T;T;T;T;T
M_CAP	Benign	0.028	D
MetaRNN	Uncertain	0.61	D;D;D;D;D
MetaSVM	Benign	-0.91	T
MutationAssessor	Uncertain	2.3	M;.;.;.;M
PrimateAI	Benign	0.42	T
PROVEAN	Uncertain	-2.5	N;.;.;.;D
REVEL	Benign	0.27
Sift	Uncertain	0.0090	D;.;.;.;D
Sift4G	Uncertain	0.051	T;D;T;D;T
Polyphen		0.98	D;.;.;.;.
Vest4		0.62
MutPred		0.64		Loss of stability (P = 0.0429);Loss of stability (P = 0.0429);Loss of stability (P = 0.0429);Loss of stability (P = 0.0429);Loss of stability (P = 0.0429);
MVP		0.85
MPC		0.36
ClinPred		0.57	D
GERP RS		2.4
Varity_R		0.90
gMVP		0.64

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: rs786203442; hg19: chr16-68772263;