16-68829754-C-G

Position:

• chr16-68829754-C-G

Variant summary

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

This summary comes from the ClinGen Evidence Repository: The c.2396C>G (p.Pro799Arg) variant is absent in the gnomAD cohort (PM2_Supporting; http://gnomad.broadinstitute.org). There is no other supporting data that meet criteria for consideration. In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): PM2_Supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA163797/MONDO:0007648/007

• Frequency: Genomes: not found (cov: 32)
• Consequence: CDH1 NM_004360.5 missense
• Clinical Significance: Uncertain significance reviewed by expert panel U:4
• Conservation: PhyloP100: 6.02

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 1 ACMG points.

• PM2: 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.2396C>G	p.Pro799Arg	missense_variant	15/16	ENST00000261769.10	NP_004351.1
CDH1	NM_001317184.2	c.2213C>G	p.Pro738Arg	missense_variant	14/15		NP_001304113.1
CDH1	NM_001317185.2	c.848C>G	p.Pro283Arg	missense_variant	15/16		NP_001304114.1
CDH1	NM_001317186.2	c.431C>G	p.Pro144Arg	missense_variant	14/15		NP_001304115.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDH1	ENST00000261769.10	c.2396C>G	p.Pro799Arg	missense_variant	15/16	1	NM_004360.5	ENSP00000261769.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: reviewed by expert panel

Submissions by phenotype

Hereditary diffuse gastric adenocarcinoma Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 28, 2024

This sequence change replaces proline, which is neutral and non-polar, with arginine, which is basic and polar, at codon 799 of the CDH1 protein (p.Pro799Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with gastric cancer (PMID: 15173255). ClinVar contains an entry for this variant (Variation ID: 140871). 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 disruptive. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on CDH1 function (PMID: 9268661, 15173255, 17510211, 22850631). 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 21, 2023

The c.2396C>G (p.Pro799Arg) variant is absent in the gnomAD cohort (PM2_Supporting; http://gnomad.broadinstitute.org). There is no other supporting data that meet criteria for consideration. In summary, the clinical significance of this variant is uncertain. ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): PM2_Supporting. -

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 11, 2024

The p.P799R variant (also known as c.2396C>G) is located in coding exon 15 of the CDH1 gene. This alteration results from a C to G substitution at nucleotide position 2396. The proline at codon 799 is replaced by arginine, an amino acid with dissimilar properties. In one study, p.P799R was identified in 1 of 35 familial gastric cancer patients in a 41-year-old patient with a mixed adenocarcinoma of the gastroesophageal junction and a family history of two maternal second degree relatives with gastric cancer, but it was not found in 50 controls. Functional studies aimed to investigate the impact of this missense change on CDH1 protein function are conflicting (Keller G et al. J Med Genet. 2004 Jun;41(6):e89; Mateus AR et al. Hum Mol Genet. 2007 Jul 1;16(13):1639-47; Mateus AR et al. Exp Cell Res. 2009 May 1;315(8):1393-402; Figueiredo J et al. Eur. J. Hum. Genet., 2013 Mar;21:301-9). Additional studies investigating the impact of this missense change on the localization and abundance of CDH1 have suggested that this alteration results in a reduction of the CDH1 protein at the cell membrane (Figueiredo J et al. Eur. J. Hum. Genet., 2013 Mar;21:301-9, Sanches JM et al. Eur. J. Hum. Genet., 2015 Aug;23:1072-9). Structural analysis of P799R exhibited higher length and angle distortions and abnormal cytoskeletal organization, suggesting the formation of very dynamic and plastic cellular interactions (Mestre T et al. Sci Rep, 2016 05;6:25101). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear. -

Familial cancer of breast Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Institute of Human Genetics, University of Leipzig Medical Center

Jan 01, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.28
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.51	D;T;.
Eigen	Pathogenic	0.75
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.84	T;T;D
M_CAP	Uncertain	0.15	D
MetaRNN	Pathogenic	0.94	D;D;D
MetaSVM	Uncertain	-0.030	T
MutationAssessor	Uncertain	2.1	M;.;.
PrimateAI	Uncertain	0.63	T
PROVEAN	Pathogenic	-6.1	D;.;D
REVEL	Pathogenic	0.72
Sift	Uncertain	0.020	D;.;D
Sift4G	Benign	0.085	T;D;D
Polyphen		1.0	D;.;.
Vest4		0.80
MutPred		0.83		Loss of glycosylation at P799 (P = 0.0419);.;.;
MVP		0.96
MPC		0.93
ClinPred		0.98	D
GERP RS		6.0
Varity_R		0.37
gMVP		0.75

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: rs587781335; hg19: chr16-68863657;