chr16-68833452-C-T

Position:

• chr16-68833452-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PP3_Moderate BS2_Supporting

The NM_004360.5(CDH1):​c.2602C>T​(p.Arg868Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000616 in 1,461,868 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: CDH1 NM_004360.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:9 B:1
• Conservation: PhyloP100: 4.08

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.851
• BS2: High AC in GnomAdExome4 at 9 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CDH1	NM_004360.5	c.2602C>T	p.Arg868Cys	missense_variant	16/16	ENST00000261769.10	NP_004351.1
CDH1	NM_001317184.2	c.2419C>T	p.Arg807Cys	missense_variant	15/15		NP_001304113.1
CDH1	NM_001317185.2	c.1054C>T	p.Arg352Cys	missense_variant	16/16		NP_001304114.1
CDH1	NM_001317186.2	c.637C>T	p.Arg213Cys	missense_variant	15/15		NP_001304115.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDH1	ENST00000261769.10	c.2602C>T	p.Arg868Cys	missense_variant	16/16	1	NM_004360.5	ENSP00000261769.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000616 AC: 9 AN: 1461868 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 727232

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000719

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000151

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:9 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary diffuse gastric adenocarcinoma Uncertain:4

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 25, 2023	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 868 of the CDH1 protein (p.Arg868Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of CDH1-related conditions (PMID: 36436516). ClinVar contains an entry for this variant (Variation ID: 220695). 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. 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Mar 23, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	European Reference Network on Genetic Tumour Risk Syndromes (ERN-GENTURIS), i3s - Instituto de Investigação e Inovação em Saúde, University of Porto	Aug 01, 2022	PM2 (PMID: 30311375) -
Uncertain significance, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Mar 03, 2023	This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk. -

Hereditary cancer-predisposing syndrome Uncertain:2 Benign:1

Uncertain significance, criteria provided, single submitter	curation	Sema4, Sema4	Oct 15, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Dec 05, 2023	This missense variant replaces arginine with cysteine at codon 868 of the CDH1 protein. To our knowledge, functional studies have not been reported for this variant. In a large breast cancer case-control study, this variant has been observed in 1/60466 cases and 5/53461 unaffected controls (PMID: 33471991). 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. -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Aug 21, 2023	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. -

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Dec 16, 2022	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 15235021, 22850631) -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2023	CDH1: PM2, PP3 -

Familial cancer of breast Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Jan 03, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.86
BayesDel_addAF	Pathogenic	0.42	D
BayesDel_noAF	Pathogenic	0.36
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.61	D;T;.
Eigen	Pathogenic	0.97
Eigen_PC	Pathogenic	0.91
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	1.0	D;D;D
M_CAP	Uncertain	0.20	D
MetaRNN	Pathogenic	0.85	D;D;D
MetaSVM	Uncertain	0.75	D
MutationAssessor	Pathogenic	3.3	M;.;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.82	D
PROVEAN	Pathogenic	-6.6	D;.;D
REVEL	Pathogenic	0.69
Sift	Pathogenic	0.0	D;.;D
Sift4G	Uncertain	0.029	D;D;D
Polyphen		1.0	D;.;.
Vest4		0.52
MutPred		0.91		Gain of ubiquitination at K870 (P = 0.0573);.;.;
MVP		0.96
MPC		1.1
ClinPred		1.0	D
GERP RS		6.2
Varity_R		0.71
gMVP		0.68

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: rs864622630; hg19: chr16-68867355; COSMIC: COSV55738596;