16-68819356-C-G

Variant names:

• chr16-68819356-C-G
• rs1181682630
• NM_004360.5:c.1642C>G

Variant summary

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

The NM_004360.5(CDH1):​c.1642C>G​(p.Leu548Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,810 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: CDH1 NM_004360.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.40

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]

ENSG00000260798 (HGNC:):

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 rank	MANE	Protein	UniProt
CDH1	NM_004360.5	c.1642C>G	p.Leu548Val	missense_variant	Exon 11 of 16	ENST00000261769.10	NP_004351.1
CDH1	NM_001317184.2	c.1459C>G	p.Leu487Val	missense_variant	Exon 10 of 15		NP_001304113.1
CDH1	NM_001317185.2	c.94C>G	p.Leu32Val	missense_variant	Exon 11 of 16		NP_001304114.1
CDH1	NM_001317186.2	c.-254-2645C>G		intron_variant	Intron 10 of 14		NP_001304115.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDH1	ENST00000261769.10	c.1642C>G	p.Leu548Val	missense_variant	Exon 11 of 16	1	NM_004360.5	ENSP00000261769.4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251484 Hom.: 0 AF XY: 0.00000736 AC XY: 1 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: 6.84e-7 AC: 1 AN: 1461810 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727198

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: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary diffuse gastric adenocarcinoma Uncertain:1

Jun 20, 2017

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has not been reported in the literature in individuals with a CDH1-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. In summary, this variant has uncertain impact on CDH1 function. The available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This sequence change replaces leucine with valine at codon 548 of the CDH1 protein (p.Leu548Val). The leucine residue is moderately conserved and there is a small physicochemical difference between leucine and valine. This variant is not present in population databases (ExAC no frequency). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	8.3
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.52	D;T;T;.;.
Eigen	Benign	-0.28
Eigen_PC	Benign	-0.56
FATHMM_MKL	Benign	0.087	N
LIST_S2	Uncertain	0.89	D;D;D;D;D
M_CAP	Uncertain	0.23	D
MetaRNN	Uncertain	0.72	D;D;D;D;D
MetaSVM	Benign	-0.42	T
MutationAssessor	Uncertain	2.8	M;.;.;.;.
PrimateAI	Benign	0.35	T
PROVEAN	Uncertain	-2.5	N;.;.;.;N
REVEL	Uncertain	0.46
Sift	Uncertain	0.0010	D;.;.;.;D
Sift4G	Uncertain	0.0040	D;D;D;D;D
Polyphen		0.95	P;.;.;.;.
Vest4		0.42
MutPred		0.80		Loss of helix (P = 0.1299);Loss of helix (P = 0.1299);.;Loss of helix (P = 0.1299);.;
MVP		0.78
MPC		0.51
ClinPred		0.97	D
GERP RS		-9.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.20
gMVP		0.43

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: rs1181682630; hg19: chr16-68853259;