16-68815760-G-GTT

Variant names:

• chr16-68815760-G-GTT
• rs1555516200
• NM_004360.5:c.1565+2_1565+3insTT

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM2 PP5_Very_Strong

The NM_004360.5(CDH1):​c.1565+2_1565+3insTT variant causes a splice region, intron change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CDH1 NM_004360.5 splice_region, intron
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 7.46
• Publications: 2 publications found

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]

CDH1 Gene-Disease associations (from GenCC):

• blepharocheilodontic syndrome 1

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, Illumina, Labcorp Genetics (formerly Invitae), G2P
• CDH1-related diffuse gastric and lobular breast cancer syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, G2P
• hereditary breast carcinoma

  Inheritance: AD Classification: DEFINITIVE Submitted by: Ambry Genetics
• hereditary diffuse gastric adenocarcinoma

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet
• cleft soft palate

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
• orofacial cleft 3

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
• blepharocheilodontic syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• familial ovarian cancer

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ENSG00000260798 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 16-68815760-G-GTT is Pathogenic according to our data. Variant chr16-68815760-G-GTT is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 463722.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDH1	NM_004360.5	c.1565+2_1565+3insTT		splice_region_variant, intron_variant	Intron 10 of 15	ENST00000261769.10	NP_004351.1
CDH1	NM_001317184.2	c.1382+2_1382+3insTT		splice_region_variant, intron_variant	Intron 9 of 14		NP_001304113.1
CDH1	NM_001317185.2	c.17+2_17+3insTT		splice_region_variant, intron_variant	Intron 10 of 15		NP_001304114.1
CDH1	NM_001317186.2	c.-255+2_-255+3insTT		splice_region_variant, 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.1565+1_1565+2insTT		splice_donor_variant, intron_variant	Intron 10 of 15	1	NM_004360.5	ENSP00000261769.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary cancer-predisposing syndrome Pathogenic:3

Oct 31, 2023

Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 21, 2024

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1565+2_1565+3insTT intronic pathogenic mutation results from the insertion of two nucleotides (TT) at positions c.1565+2 to c.1565+3, which is two nucleotides after coding exon 10 of the CDH1 gene. This mutation was reported in a large Danish family with gastric cancer and a history suggesting HDGC (Bardram L et al. Fam. Cancer, 2014 Jun;13:231-42). Bardram et al. further assessed the functional significance of this alteration using a mini-gene assay and showed this alteration results in a deletion of exon 10. Authors also note that seven asymptomatic mutation carriers underwent prophylactic gastrectomy and small foci of diffuse gastric cancer were found in all patients. Based on the available evidence, c.1565+2_1565+3insTT is classified as a pathogenic mutation. -

May 05, 2020

Color Diagnostics, LLC DBA Color Health

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant causes the insertion of two nucleotides in intron 10 splice donor site of the CDH1 gene. This variant is also known as c.1565+3insTT in the literature. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing, and an RNA mini-gene study showed that the variant resulted in two aberrant splicing products predicted to create absent or non-functional protein product (PMID: 24389957). This variant has been reported in diffuse gastric cancer affected individuals from two families (PMID: 24389957, 31296550), and it has been shown that this variant segregates with disease in multiple affected members in one of the two families (PMID: 24389957). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -

not provided Pathogenic:1

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary diffuse gastric adenocarcinoma Pathogenic:1

May 22, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change falls in intron 10 of the CDH1 gene. It does not directly change the encoded amino acid sequence of the CDH1 protein. It affects a nucleotide within the consensus splice site. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individuals with diffuse gastric cancer (PMID: 24389957; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 463722). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 24389957). For these reasons, this variant has been classified as Pathogenic. -

CDH1-related diffuse gastric and lobular breast cancer syndrome Pathogenic:1

Dec 16, 2024

Clinical Genetics Laboratory, Skane University Hospital Lund

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The patient is heterozygous for the variant. ACMG criteria used: PVS1_Strong, PS4, PM2, PM5_Supporting -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.5
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1555516200; hg19: chr16-68849663;