16-68822032-TCTG-T

Variant names:

• chr16-68822032-TCTG-T
• rs1555516823
• NM_004360.5:c.1747_1749delCTG

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PM4_Supporting

The NM_004360.5(CDH1):​c.1747_1749delCTG​(p.Leu583del) variant causes a conservative inframe deletion change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: CDH1 NM_004360.5 conservative_inframe_deletion
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 4.53

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_004360.5. Strenght limited to Supporting due to length of the change: 1aa.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDH1	NM_004360.5	c.1747_1749delCTG	p.Leu583del	conservative_inframe_deletion	Exon 12 of 16	ENST00000261769.10	NP_004351.1
CDH1	NM_001317184.2	c.1564_1566delCTG	p.Leu522del	conservative_inframe_deletion	Exon 11 of 15		NP_001304113.1
CDH1	NM_001317185.2	c.199_201delCTG	p.Leu67del	conservative_inframe_deletion	Exon 12 of 16		NP_001304114.1
CDH1	NM_001317186.2	c.-219_-217delCTG		5_prime_UTR_variant	Exon 11 of 15		NP_001304115.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDH1	ENST00000261769.10	c.1747_1749delCTG	p.Leu583del	conservative_inframe_deletion	Exon 12 of 16	1	NM_004360.5	ENSP00000261769.4

Frequencies

GnomAD3 genomes Cov.: 31

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:1

Nov 29, 2017

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1747_1749delCTG variant in the CDH1 gene has not been reported previously as a germline pathogenic variant nor as a benign variant, to our knowledge. This variant causes an in-frame deletion of codon Leucine 583, denoted p.Leu583del. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. The c.1747_1749delCTG variant is not observed in large population cohorts (Lek et al., 2016). We interpret c.1747_1749delCTG as a variant of uncertain significance. -

Hereditary cancer-predisposing syndrome Uncertain:1

Jul 26, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1747_1749delCTG variant (also known as p.L583del) is located in coding exon 12 of the CDH1 gene. This variant results from an in-frame CTG deletion at nucleotide positions 1747 to 1749. This results in the in-frame deletion of a leucine at codon 583. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis (Choi Y et al. PLoS ONE. 2012; 7(10):e46688). Based on the available evidence, the clinical significance of this variant remains unclear. -

Computational scores

Source: dbNSFP v4.3

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: rs1555516823; hg19: chr16-68855935;