rs1555518221

chr16-68833320-GC-Gchr16-68833320-GC-GCC

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1_Strong PM2 PP5_Moderate

The NM_004360.5(CDH1):c.2474del(p.Pro825ArgfsTer21) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. A824A) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CDH1 NM_004360.5 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 6.15

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 Likely_pathogenic. Variant got 8 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 10 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 16-68833320-GC-G is Pathogenic according to our data. Variant chr16-68833320-GC-G is described in ClinVar as [Pathogenic]. Clinvar id is 656340.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDH1	NM_004360.5	c.2474del	p.Pro825ArgfsTer21	frameshift_variant	16/16	ENST00000261769.10
CDH1	NM_001317184.2	c.2291del	p.Pro764ArgfsTer21	frameshift_variant	15/15
CDH1	NM_001317185.2	c.926del	p.Pro309ArgfsTer21	frameshift_variant	16/16
CDH1	NM_001317186.2	c.509del	p.Pro170ArgfsTer21	frameshift_variant	15/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDH1	ENST00000261769.10	c.2474del	p.Pro825ArgfsTer21	frameshift_variant	16/16	1	NM_004360.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary diffuse gastric adenocarcinoma Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Nov 21, 2020

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the C-terminus of the CDH1 protein. Other variant(s) that disrupt this region (p.Pro826Alafs*3, p.Glu836*) have been determined to be pathogenic (PMID: 29798843, Invitae). This suggests that variants that disrupt this region of the protein are likely to be causative of disease. Experimental studies and prediction algorithms are not available for this variant, and the functional significance of the affected amino acid(s) is currently unknown. This variant has not been reported in the literature in individuals with CDH1-related conditions. ClinVar contains an entry for this variant (Variation ID: 656340). This variant is not present in population databases (ExAC no frequency). This sequence change results in a premature translational stop signal in the CDH1 gene (p.Pro825Argfs*21). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 58 amino acids of the CDH1 protein. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1555518221; hg19: chr16-68867223;