chr16-68815760-G-A

Position:

• chr16-68815760-G-A

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PS4 PVS1_Strong PP1_Strong PM5_Supporting PM2_Supporting PS3_Moderate

This summary comes from the ClinGen Evidence Repository: The c.1565+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 has been reported in at least six families meeting HDGC clinical criteria (PS4; PMID:26182300, SCV000149752.12 and internal laboratory contributor). This variant was also found to co-segregate with disease in multiple affected family members, with nine meioses observed across at least five families (PP1_Strong; SCV000149752.12 and internal laboratory contributor). The c.1565+1G>A allele was demonstrated to alter splicing through RNASeq analysis of mRNA from an affected carrier (PS3_Moderate; PMID:31843900). In summary, this variant meets criteria to be classified as 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, PS4, PP1_Strong, PS3_Moderate, PM2_Supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CV127915/MONDO:0007648/007

• Frequency: Genomes: not found (cov: 32)
• Consequence: CDH1 ENST00000261769.10 splice_donor
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic reviewed by expert panel P:13 O:4
• Conservation: PhyloP100: 9.33

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]

(HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 16 ACMG points.

• PVS1: For more information check the summary or visit ClinGen Evidence Repository.
• PS3: 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.
• PP1: 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.1565+1G>A		splice_donor_variant		ENST00000261769.10	NP_004351.1
CDH1	NM_001317184.2	c.1382+1G>A		splice_donor_variant			NP_001304113.1
CDH1	NM_001317185.2	c.17+1G>A		splice_donor_variant			NP_001304114.1
CDH1	NM_001317186.2	c.-255+1G>A		splice_donor_variant			NP_001304115.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDH1	ENST00000261769.10	c.1565+1G>A		splice_donor_variant		1	NM_004360.5	ENSP00000261769	P1
	ENST00000563916.1	n.264-101C>T		intron_variant, non_coding_transcript_variant		4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:13 Other:4

Revision: reviewed by expert panel

Submissions by phenotype

Hereditary diffuse gastric adenocarcinoma Pathogenic:5 Other:3

Likely pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Mar 07, 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 05, 2023	This sequence change affects a donor splice site in intron 10 of the CDH1 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site 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). This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individuals with breast cancer and diffuse gastric cancer (PMID: 18046629, 26182300, 27064202, 27153395). ClinVar contains an entry for this variant (Variation ID: 127915). Studies have shown that disruption of this splice site is associated with inconclusive levels of altered splicing (Invitae). For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	European Reference Network on Genetic Tumour Risk Syndromes (ERN-GENTURIS), i3s - Instituto de Investigação e Inovação em Saúde, University of Porto	Aug 01, 2022	PVS1_Strong; PS4_Moderate; PM2 (PMID: 30311375) -
not provided, no classification provided	phenotyping only	GenomeConnect - Invitae Patient Insights Network	-	Variant interpreted as Pathogenic and reported on 12-10-2015 by Lab Myriad. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Feb 22, 2023	_x000D_ Criteria applied: PVS1, PS4_MOD, PM2_SUP -
not provided, no classification provided	phenotyping only	GenomeConnect, ClinGen	-	Variant interpreted as Pathogenic and reported on 07-15-2020 by Lab or GTR ID 61756. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -
Pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Oct 16, 2017	- -
not provided, no classification provided	phenotyping only	GenomeConnect - No Stomach For Cancer	-	Variant interpreted as Pathogenic and reported on 09-30-2011 by Lab or GTR ID 61756. GenomeConnect- No Stomach for Cancer assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. -

Familial cancer of breast Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Jun 07, 2023	- -
Pathogenic, criteria provided, single submitter	research	Centre for Mendelian Genomics, University Medical Centre Ljubljana	Dec 09, 2022	PVS1_STR, PS4_STR, PS3, PM2_SUP, PP1 -
Pathogenic, criteria provided, single submitter	clinical testing	Department of Molecular Diagnostics, Institute of Oncology Ljubljana	Apr 02, 2020	- -

Hereditary cancer-predisposing syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Jan 06, 2023	The c.1565+1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide after coding exon 10 of the CDH1 gene. This mutation has been reported as pathogenic in a lobular breast cancer patient, whose family history was significant primarily for multiple breast cancers and also one early-onset gastric cancer (Schrader KA et al. Fam Cancer. 2008;7:73-82). In addition, a second splicing mutation at this position, c.1565+1G>T, has been detected in a diffuse gastric cancer family (Humar B et al. Hum Mutat. 2002;19(5):518-25). Of note, this mutation is also called IVS10+1G>A in published literature. In silico splice site analysis predicts that this alteration will weaken the native splice donor site and will result in the creation or strengthening of a novel splice donor site. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). In addition to the clinical data presented in the literature, 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jan 20, 2022	This variant causes a G>A nucleotide substitution at the canonical +1 position of intron 10 splice donor of the CDH1 gene. RNA studies have shown that this variant results in the use of a cryptic splice site, resulting in a 6 bp message insertion and premature stop at codon 523 (PMID: 31843900). This variant has been reported in individuals affected with breast and diffuse gastric cancer (PMID: 18046629, 24506336, 26182300, 26681312, 27064202, 27153395, 33322525; Lowstuter 2017, DOI: 10.1200/PO.16.00021). Different DNA subsitution variants at the +1 G nucleotide position have also been reported in individuals and families affected with diffuse gastric cancer (PMID: 11968084, 18788075, 26182300). 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. Based on the available evidence, this variant is classified as Pathogenic. -

not provided Pathogenic:1 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jul 28, 2023	Canonical splice site variant in a gene for which loss-of-function is a known mechanism of disease; Observed in families with a history of cleft lip and palate in published literature (Green et al., 2022); Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 20373070, 25525159, 24506336, 27064202, 18046629, 27153395, 25986922, 26182300, 30745422, 26681312, 31986421, 30641862, 36436516, 34949788, 36246616) -
not provided, no classification provided	research	MutSpliceDB: a database of splice sites variants effects on splicing, NIH	-	- -

Familial cancer of breast;C1708349:Hereditary diffuse gastric adenocarcinoma Pathogenic:1

Pathogenic, no assertion criteria provided

research

King Laboratory, University of Washington

Sep 01, 2019

- -

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

Pathogenic, reviewed by expert panel

curation

ClinGen CDH1 Variant Curation Expert Panel

Aug 30, 2023

The c.1565+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 has been reported in at least six families meeting HDGC clinical criteria (PS4; PMID: 26182300, SCV000149752.12 and internal laboratory contributor). This variant was also found to co-segregate with disease in multiple affected family members, with nine meioses observed across at least five families (PP1_Strong; SCV000149752.12 and internal laboratory contributor). The c.1565+1G>A allele was demonstrated to alter splicing through RNASeq analysis of mRNA from an affected carrier (PS3_Moderate; PMID: 31843900). In summary, this variant meets criteria to be classified as 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, PS4, PP1_Strong, PS3_Moderate, PM2_Supporting. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.42
CADD	Pathogenic	36
DANN	Uncertain	1.0
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	1.0	D
MutationTaster	Benign	1.0	D;D
GERP RS		5.7

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_DG_spliceai		0.74		Position offset: 5
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: rs587780113; hg19: chr16-68849663; COSMIC: COSV55731158; COSMIC: COSV55731158;