rs886041161

Positions:

• chr16-68819426-G-A
• chr16-68819426-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PVS1_Strong PM5_Supporting PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The c.1711+1G>A variant is a canonical splice variant predicted to result in a truncated or absent protein (PVS1_Strong). The variant is absent in the gnomAD cohort. (PM2_Supporting; http://gnomad.broadinstitute.org). This variant is at +1 donor site variant with other likely pathogenic canonical splicing variants curated at the same splice site (PM5_Supporting). Therefore, this variant meets criteria to be classified as likely pathogenic based on the ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): PVS1_Strong, PM2_Supporting, PM5_Supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA396465476/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:6
• Conservation: PhyloP100: 8.84

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 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PVS1: 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/exons	MANE	Protein	UniProt
CDH1	NM_004360.5	c.1711+1G>A		splice_donor_variant, intron_variant		ENST00000261769.10	NP_004351.1
CDH1	NM_001317184.2	c.1528+1G>A		splice_donor_variant, intron_variant			NP_001304113.1
CDH1	NM_001317185.2	c.163+1G>A		splice_donor_variant, intron_variant			NP_001304114.1
CDH1	NM_001317186.2	c.-254-2575G>A		intron_variant			NP_001304115.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDH1	ENST00000261769.10	c.1711+1G>A		splice_donor_variant, intron_variant		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:6

Revision: reviewed by expert panel

Submissions by phenotype

not provided Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 26, 2022	Canonical splice site variant predicted to result in a null allele in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Observed in at least one individual undergoing next-generation sequencing for hereditary disorders (LaDuca 2017); This variant is associated with the following publications: (PMID: 28152038) -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jan 10, 2023	This variant disrupts a canonical splice-donor site and interferes with normal CDH1 mRNA splicing. This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In the published literature, the variant has been reported in an individual with a personal or family history of gastric cancer (PMID: 31077828 (2020)). Based on the available information, this variant is classified as pathogenic. -

Hereditary diffuse gastric adenocarcinoma Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 11, 2023	This sequence change affects a donor splice site in intron 11 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. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with CDH1-related conditions. ClinVar contains an entry for this variant (Variation ID: 428628). Studies have shown that disruption of this splice site results in skipping of exon 11 and introduces a premature termination codon (Invitae). The resulting mRNA is expected to undergo nonsense-mediated decay. 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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Jun 14, 2023	This variant is considered likely pathogenic. This variant occurs within a consensus splice junction and is predicted to result in abnormal mRNA splicing of either an out-of-frame exon or an in-frame exon necessary for protein stability and/or normal function. -

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

Likely pathogenic, reviewed by expert panel

curation

ClinGen CDH1 Variant Curation Expert Panel

Aug 04, 2023

The c.1711+1G>A variant is a canonical splice variant predicted to result in a truncated or absent protein (PVS1_Strong). The variant is absent in the gnomAD cohort. (PM2_Supporting; http://gnomad.broadinstitute.org). This variant is at +1 donor site variant with other likely pathogenic canonical splicing variants curated at the same splice site (PM5_Supporting). Therefore, this variant meets criteria to be classified as likely pathogenic based on the ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): PVS1_Strong, PM2_Supporting, PM5_Supporting. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 26, 2021

The c.1711+1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide after coding exon 11 of the CDH1 gene. A different alteration at this splice site, c.1711+1G>C, has been reported in an individual with lobular breast cancer and in a cleft lip/palate (CLP) / hereditary diffuse gastric cancer (HDGC) family (Sarrió D et al. Int J Cancer, 2003 Aug;106:208-15, Obermair F et al. Fam Cancer, 2019 04;18:253-260). 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 a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.19
CADD	Pathogenic	27
DANN	Uncertain	0.99
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.87
FATHMM_MKL	Pathogenic	0.99	D
GERP RS		5.5

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.93
SpliceAI score (max)		0.99		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.99		Position offset: -1

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

Publications

LitVar

Other links and lift over

dbSNP: rs886041161; hg19: chr16-68853329; COSMIC: COSV99028507; COSMIC: COSV99028507;