16-68812265-T-C

Position:

• chr16-68812265-T-C

Variant summary

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

This summary comes from the ClinGen Evidence Repository: This c.1137+2T>C variant occurs at the canonical donor splice site of exon 8 (PVS1_strong, PM5_Supporting). This variant is absent from populations in gnomAD (PM2_Supporting; http://gnomad.broadinstitute.org) and has been observed in at least one individual meeting IGCLC criteria for HDGC (PS4_supporting; internal laboratory data). In summary, this variant meets criteria to be classified as likely pathogenic based on ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel: PVS1_strong, PM2_Supporting, PS4_supporting, PM5_Supporting (Variant Interpretation Guidelines Version 3.1). LINK:https://erepo.genome.network/evrepo/ui/classification/CA194301/MONDO:0007648/007

• Frequency: Genomes: not found (cov: 32)
• Consequence: CDH1 NM_004360.5 splice_donor
• Scores: Splicing: ADA: 0.9712
• Clinical Significance: Likely pathogenic reviewed by expert panel P:4
• Conservation: PhyloP100: 5.82

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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDH1	NM_004360.5	c.1137+2T>C		splice_donor_variant		ENST00000261769.10
CDH1	NM_001317184.2	c.1137+2T>C		splice_donor_variant
CDH1	NM_001317185.2	c.-479+2T>C		splice_donor_variant
CDH1	NM_001317186.2	c.-683+2T>C		splice_donor_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDH1	ENST00000261769.10	c.1137+2T>C		splice_donor_variant		1	NM_004360.5	P1

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

Likely pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Oct 08, 2014	The c.1137+2T>C intronic variant results from a T to C substitution two nucleotides after coding exon 8 in the CDH1 gene. This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6498 samples (12996 alleles) with coverage at this position. To date, this alteration has been detected with an allele frequency of approximately 0.002% (greater than 45000 alleles tested) in our clinical cohort (includes this individual).This nucleotide position is highly conserved in available vertebrate species. Using the MaxEntScan, BDGP, and ESEfinder splice site prediction tools, this alteration is predicted to abolish the native donor splice site; however, direct evidence is unavailable. Alterations that disrupt the canonical splice donor site are typically deleterious in nature (ACMG Recommendations for Standards for Interpretation and Reporting of Sequence Variations. Revision 2007. Genet Med. 2008;10:294). As such, the c.1137+2T>C variant is classified as likely pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	May 26, 2020	This variant causes a T to C nucleotide substitution at the canonical +2 position of intron 8 splice donor site of the CDH1 gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. Although functional studies have not been reported for this variant, this variant is expected to result in an absent or non-functional protein product. This variant has been reported in an individual affected with breast cancer (PMID: 31296550). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). A different variant affecting the same splice donor site c.1137+1G>A is known to be disease-causing (Clinvar variation ID: 233979). Loss of CDH1 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Likely Pathogenic. -

Hereditary diffuse gastric adenocarcinoma Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2020

This variant is not present in population databases (ExAC no frequency). This sequence change affects a donor splice site in intron 8 of the CDH1 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. Disruption of this splice site has been observed in individuals with diffuse gastric cancer (PMID: 10477433, Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 186267). For these reasons, this variant has been classified as Pathogenic. Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in CDH1 are known to be pathogenic (PMID: 15235021, 20373070). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. -

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

Likely pathogenic, reviewed by expert panel

curation

ClinGen CDH1 Variant Curation Expert Panel

Oct 23, 2023

This c.1137+2T>C variant occurs at the canonical donor splice site of exon 8 (PVS1_strong, PM5_Supporting). This variant is absent from populations in gnomAD (PM2_Supporting; http://gnomad.broadinstitute.org) and has been observed in at least one individual meeting IGCLC criteria for HDGC (PS4_supporting; internal laboratory data). In summary, this variant meets criteria to be classified as likely pathogenic based on ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel: PVS1_strong, PM2_Supporting, PS4_supporting, PM5_Supporting (Variant Interpretation Guidelines Version 3.1). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.010
CADD	Pathogenic	27
DANN	Uncertain	0.98
Eigen	Pathogenic	0.95
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Uncertain	0.96	D
MutationTaster	Benign	1.0	D;D
GERP RS		5.7

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.97
dbscSNV1_RF	Benign	0.56
SpliceAI score (max)		0.99		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.99		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: rs786202817; hg19: chr16-68846168;