rs1060501238

Positions:

• chr16-68812222-A-C
• chr16-68812222-A-G
• chr16-68812222-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM1 BS2_Supporting

The NM_004360.5(CDH1):​c.1096A>C​(p.Thr366Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000616 in 1,461,846 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: CDH1 NM_004360.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 1.67

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.

• PM1: In a domain Cadherin 2 (size 112) in uniprot entity CADH1_HUMAN there are 7 pathogenic changes around while only 3 benign (70%) in NM_004360.5
• 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.1096A>C	p.Thr366Pro	missense_variant	8/16	ENST00000261769.10	NP_004351.1
CDH1	NM_001317184.2	c.1096A>C	p.Thr366Pro	missense_variant	8/15		NP_001304113.1
CDH1	NM_001317185.2	c.-520A>C		5_prime_UTR_variant	8/16		NP_001304114.1
CDH1	NM_001317186.2	c.-724A>C		5_prime_UTR_variant	8/15		NP_001304115.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDH1	ENST00000261769.10	c.1096A>C	p.Thr366Pro	missense_variant	8/16	1	NM_004360.5	ENSP00000261769.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251476 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135916

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000616 AC: 9 AN: 1461846 Hom.: 0 Cov.: 32 AF XY: 0.00000963 AC XY: 7 AN XY: 727228

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000104

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary diffuse gastric adenocarcinoma Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Apr 28, 2023

ClinVar contains an entry for this variant (Variation ID: 941549). This variant has not been reported in the literature in individuals affected with CDH1-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.003%). This sequence change replaces threonine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 366 of the CDH1 protein (p.Thr366Pro). 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. -

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 15, 2024

The p.T366P variant (also known as c.1096A>C), located in coding exon 8 of the CDH1 gene, results from an A to C substitution at nucleotide position 1096. The threonine at codon 366 is replaced by proline, an amino acid with highly similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.46
BayesDel_addAF	Benign	-0.079	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	20
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.58	D;T;T;.;.
Eigen	Benign	-0.036
Eigen_PC	Benign	-0.30
FATHMM_MKL	Benign	0.35	N
LIST_S2	Benign	0.82	T;T;T;T;T
M_CAP	Benign	0.069	D
MetaRNN	Uncertain	0.60	D;D;D;D;D
MetaSVM	Benign	-0.47	T
MutationAssessor	Uncertain	2.5	M;.;.;.;M
PrimateAI	Benign	0.32	T
PROVEAN	Pathogenic	-4.6	D;.;.;.;D
REVEL	Benign	0.27
Sift	Uncertain	0.010	D;.;.;.;D
Sift4G	Uncertain	0.013	D;D;D;D;D
Polyphen		0.89	P;.;.;.;.
Vest4		0.41
MutPred		0.54		Loss of glycosylation at T366 (P = 0.0603);Loss of glycosylation at T366 (P = 0.0603);Loss of glycosylation at T366 (P = 0.0603);Loss of glycosylation at T366 (P = 0.0603);Loss of glycosylation at T366 (P = 0.0603);
MVP		0.81
MPC		0.35
ClinPred		0.95	D
GERP RS		-0.54
Varity_R		0.95
gMVP		0.81

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs1060501238; hg19: chr16-68846125;