16-68738307-G-C

Position:

• chr16-68738307-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_004360.5(CDH1):​c.59G>C​(p.Trp20Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000143 in 1,398,052 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: CDH1 NM_004360.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 1.11

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: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.32657802).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CDH1	NM_004360.5	c.59G>C	p.Trp20Ser	missense_variant	2/16	ENST00000261769.10	NP_004351.1
CDH1	NM_001317184.2	c.59G>C	p.Trp20Ser	missense_variant	2/15		NP_001304113.1
CDH1	NM_001317185.2	c.-1557G>C		5_prime_UTR_variant	2/16		NP_001304114.1
CDH1	NM_001317186.2	c.-1761G>C		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.59G>C	p.Trp20Ser	missense_variant	2/16	1	NM_004360.5	ENSP00000261769.4
CDH1	ENST00000422392.6	c.59G>C	p.Trp20Ser	missense_variant	2/15	1		ENSP00000414946.2
CDH1	ENST00000566612.5	n.59G>C		non_coding_transcript_exon_variant	2/15	1		ENSP00000454782.1
CDH1	ENST00000566510.5	n.59G>C		non_coding_transcript_exon_variant	2/15	5		ENSP00000458139.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000143 AC: 2 AN: 1398052 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 689674

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: 0.00000186

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

Jan 08, 2020

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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with CDH1-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change replaces tryptophan with serine at codon 20 of the CDH1 protein (p.Trp20Ser). The tryptophan residue is weakly conserved and there is a large physicochemical difference between tryptophan and serine. -

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 24, 2020

The p.W20S variant (also known as c.59G>C), located in coding exon 2 of the CDH1 gene, results from a G to C substitution at nucleotide position 59. The tryptophan at codon 20 is replaced by serine, an amino acid with highly dissimilar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	14
DANN	Benign	0.60
DEOGEN2	Uncertain	0.44	T;T;T;.;.
Eigen	Benign	-0.82
Eigen_PC	Benign	-0.77
FATHMM_MKL	Benign	0.21	N
LIST_S2	Benign	0.52	T;T;T;T;T
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.33	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.1	L;.;.;.;L
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-1.1	N;.;.;.;N
REVEL	Benign	0.074
Sift	Benign	0.72	T;.;.;.;T
Sift4G	Benign	0.76	T;T;T;T;T
Polyphen		0.0010	B;.;.;.;.
Vest4		0.54
MutPred		0.55		Gain of disorder (P = 0);Gain of disorder (P = 0);Gain of disorder (P = 0);Gain of disorder (P = 0);Gain of disorder (P = 0);
MVP		0.66
MPC		0.40
ClinPred		0.027	T
GERP RS		3.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.17
gMVP		0.37

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		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: rs121964875; hg19: chr16-68772210;