16-68811861-T-C

Variant names:

• chr16-68811861-T-C
• rs1060501237
• NM_004360.5:c.1008+2T>C

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM5_Supporting PS4_Supporting PM2_Supporting PVS1_Strong

This summary comes from the ClinGen Evidence Repository: The c.1008+2T>C variant occurs at the canonical splice donor site of exon 7 and is predicted to result in a truncated or absent protein (PVS1_strong, PM5_Supporting). This variant is absent from populations in gnomAD (PM2_Supporting; https://gnomad.broadinstitute.org/). In addition, this variant has been identified in one family meeting IGCLC criteria for HDGC (PS4_supporting; SCV000545440.4). Although functional studies have not been reported for this variant, CDH1 c.1008G>T (p.Glu336Asp), affecting the last nucleotide in exon 7, has been shown to result in abnormal splicing (PMID:31642931). In summary, this variant meets criteria to be classified as likely pathogenic based on ACMG/AMP criteria as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): PVS1_strong, PM2_Supporting, PS4_supporting, PM5_Supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA16615376/MONDO:0007648/007

• Frequency: Genomes: not found (cov: 32)
• Consequence: CDH1 NM_004360.5 splice_donor, intron
• Scores: Splicing: ADA: 0.9999
• Clinical Significance: Likely pathogenic reviewed by expert panel P:4
• Conservation: PhyloP100: 7.67

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 7 ACMG points.

• PVS1: For more information check the summary or visit ClinGen Evidence Repository.
• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• PM5: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDH1	NM_004360.5	c.1008+2T>C		splice_donor_variant, intron_variant	Intron 7 of 15	ENST00000261769.10	NP_004351.1
CDH1	NM_001317184.2	c.1008+2T>C		splice_donor_variant, intron_variant	Intron 7 of 14		NP_001304113.1
CDH1	NM_001317185.2	c.-608+2T>C		splice_donor_variant, intron_variant	Intron 7 of 15		NP_001304114.1
CDH1	NM_001317186.2	c.-812+2T>C		splice_donor_variant, intron_variant	Intron 7 of 14		NP_001304115.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDH1	ENST00000261769.10	c.1008+2T>C		splice_donor_variant, intron_variant	Intron 7 of 15	1	NM_004360.5	ENSP00000261769.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:4

Revision: reviewed by expert panel

Submissions by phenotype

Hereditary cancer-predisposing syndrome Pathogenic:2

Aug 03, 2020

Color Diagnostics, LLC DBA Color Health

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant causes a T to C nucleotide substitution at the +2 position of intron 7 of the CDH1 gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of CDH1 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Likely Pathogenic. -

Mar 10, 2025

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1008+2T>C intronic variant results from a T to C substitution two nucleotides after coding exon 7 in the CDH1 gene. This variant was reported in individual(s) with features consistent with CDH1-related diffuse gastric and lobular breast cancer (DGLBC). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as likely pathogenic. -

Hereditary diffuse gastric adenocarcinoma Pathogenic:1

Jun 07, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Studies have shown that disruption of this splice site results in activation of a cryptic splice site and introduces a premature termination codon (Invitae). The resulting mRNA is expected to undergo nonsense-mediated decay. ClinVar contains an entry for this variant (Variation ID: 406652). This variant has not been reported in the literature in individuals affected with CDH1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change affects a donor splice site in intron 7 of the CDH1 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or disrupted protein product. -

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

Aug 24, 2023

ClinGen CDH1 Variant Curation Expert Panel

Significance: Likely pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The c.1008+2T>C variant occurs at the canonical splice donor site of exon 7 and is predicted to result in a truncated or absent protein (PVS1_strong, PM5_Supporting). This variant is absent from populations in gnomAD (PM2_Supporting; https://gnomad.broadinstitute.org/). In addition, this variant has been identified in one family meeting IGCLC criteria for HDGC (PS4_supporting; SCV000545440.4). Although functional studies have not been reported for this variant, CDH1 c.1008G>T (p.Glu336Asp), affecting the last nucleotide in exon 7, has been shown to result in abnormal splicing (PMID: 31642931). In summary, this variant meets criteria to be classified as likely pathogenic based on ACMG/AMP criteria as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): PVS1_strong, PM2_Supporting, PS4_supporting, PM5_Supporting. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.29
CADD	Pathogenic	31
DANN	Uncertain	0.99
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.97
FATHMM_MKL	Pathogenic	0.97	D
GERP RS		5.5

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.92
SpliceAI score (max)		0.95		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.95		Position offset: -2

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

Publications

LitVar

Other links and lift over

dbSNP: rs1060501237; hg19: chr16-68845764;