rs876659762

Positions:

• chr16-68815557-G-A
• chr16-68815557-G-C
• chr16-68815557-G-T

Variant summary

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

This summary comes from the ClinGen Evidence Repository: The c.1363G>A (NM_004360.5) variant in CDH1 is a missense variant predicted to predicted to cause substitution of Ala by Thr at amino acid 455 (p.Ala455Thr). This variant was observed in more than three heterozygous individuals with no DGC, LBC or SRC tumours and whose families do not suggest HDGC (BS2_Supporting; Invitae, Ambry, GeneDx). 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/CA396462787/MONDO:0100488/007

• Frequency: Genomes: not found (cov: 32)
• Consequence: CDH1 ENST00000261769.10 missense
• Clinical Significance: Uncertain significance reviewed by expert panel U:3 B:1
• Conservation: PhyloP100: 0.00500

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]

(HGNC:):

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/exons	MANE	Protein	UniProt
CDH1	NM_004360.5	c.1363G>A	p.Ala455Thr	missense_variant	10/16	ENST00000261769.10	NP_004351.1
CDH1	NM_001317184.2	c.1180G>A	p.Ala394Thr	missense_variant	9/15		NP_001304113.1
CDH1	NM_001317185.2	c.-186G>A		5_prime_UTR_variant	10/16		NP_001304114.1
CDH1	NM_001317186.2	c.-457G>A		5_prime_UTR_variant	10/15		NP_001304115.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDH1	ENST00000261769.10	c.1363G>A	p.Ala455Thr	missense_variant	10/16	1	NM_004360.5	ENSP00000261769	P1
	ENST00000563916.1	n.347+19C>T		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3 Benign:1

Revision: reviewed by expert panel

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 16, 2016	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	Color Diagnostics, LLC DBA Color Health	Dec 04, 2023	This missense variant replaces alanine with threonine at codon 455 of the CDH1 protein. To our knowledge, functional studies have not been reported for this variant, however threonine is found in multiple mammalian species, suggesting that this missense change does not affect protein function. 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. -

Hereditary diffuse gastric adenocarcinoma Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 13, 2023

This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 455 of the CDH1 protein (p.Ala455Thr). 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: 481700). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The threonine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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

Uncertain significance, reviewed by expert panel

curation

ClinGen CDH1 Variant Curation Expert Panel

Aug 02, 2023

The c.1363G>A (NM_004360.5) variant in CDH1 is a missense variant predicted to predicted to cause substitution of Ala by Thr at amino acid 455 (p.Ala455Thr). This variant was observed in more than three heterozygous individuals with no DGC, LBC or SRC tumours and whose families do not suggest HDGC (BS2_Supporting; Invitae, Ambry, GeneDx). 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) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	1.2
DANN	Benign	0.56
DEOGEN2	Benign	0.15	T;T;T;.;.
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.035	N
LIST_S2	Benign	0.69	T;T;T;T;T
M_CAP	Benign	0.0088	T
MetaRNN	Benign	0.088	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-1.0	N;.;.;.;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.27	T
PROVEAN	Benign	0.36	N;.;.;.;N
REVEL	Benign	0.062
Sift	Benign	0.52	T;.;.;.;T
Sift4G	Benign	0.69	T;T;T;T;T
Polyphen		0.0	B;.;.;.;.
Vest4		0.11
MutPred		0.47		Loss of sheet (P = 0.302);Loss of sheet (P = 0.302);.;Loss of sheet (P = 0.302);.;
MVP		0.66
MPC		0.25
ClinPred		0.026	T
GERP RS		-2.3
Varity_R		0.059
gMVP		0.22

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs876659762; hg19: chr16-68849460;