16-68738336-C-T

Position:

• chr16-68738336-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_004360.5(CDH1):​c.88C>T​(p.Pro30Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000719 in 1,391,190 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P30T) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: CDH1 NM_004360.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.584

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CDH1	NM_004360.5	c.88C>T	p.Pro30Ser	missense_variant	2/16	ENST00000261769.10	NP_004351.1
CDH1	NM_001317184.2	c.88C>T	p.Pro30Ser	missense_variant	2/15		NP_001304113.1
CDH1	NM_001317185.2	c.-1528C>T		5_prime_UTR_variant	2/16		NP_001304114.1
CDH1	NM_001317186.2	c.-1732C>T		5_prime_UTR_variant	2/15		NP_001304115.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDH1	ENST00000261769.10	c.88C>T	p.Pro30Ser	missense_variant	2/16	1	NM_004360.5	ENSP00000261769.4
CDH1	ENST00000422392.6	c.88C>T	p.Pro30Ser	missense_variant	2/15	1		ENSP00000414946.2
CDH1	ENST00000566612.5	n.88C>T		non_coding_transcript_exon_variant	2/15	1		ENSP00000454782.1
CDH1	ENST00000566510.5	n.88C>T		non_coding_transcript_exon_variant	2/15	5		ENSP00000458139.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.19e-7 AC: 1 AN: 1391190 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 686076

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.31e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary diffuse gastric adenocarcinoma Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 01, 2021

This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 30 of the CDH1 protein (p.Pro30Ser). 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. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The serine 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Uncertain	0.039	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	18
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.43	T;T;T;.;.
Eigen	Benign	-0.022
Eigen_PC	Benign	-0.22
FATHMM_MKL	Benign	0.095	N
LIST_S2	Benign	0.76	T;T;T;T;T
M_CAP	Uncertain	0.16	D
MetaRNN	Uncertain	0.66	D;D;D;D;D
MetaSVM	Uncertain	-0.087	T
MutationAssessor	Uncertain	2.9	M;.;.;.;M
PrimateAI	Benign	0.39	T
PROVEAN	Uncertain	-3.0	D;.;.;.;D
REVEL	Uncertain	0.46
Sift	Benign	0.043	D;.;.;.;T
Sift4G	Benign	0.076	T;T;T;T;T
Polyphen		0.99	D;.;.;.;.
Vest4		0.37
MutPred		0.77		Gain of relative solvent accessibility (P = 0.0082);Gain of relative solvent accessibility (P = 0.0082);Gain of relative solvent accessibility (P = 0.0082);Gain of relative solvent accessibility (P = 0.0082);Gain of relative solvent accessibility (P = 0.0082);
MVP		0.96
MPC		0.28
ClinPred		0.66	D
GERP RS		3.8
Varity_R		0.16
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

No publications associated with this variant yet.

Other links and lift over

hg19: chr16-68772239; COSMIC: COSV55739461; COSMIC: COSV55739461;