16-68812264-G-A

Position:

chr16-68812264-G-A

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PS4PS3PM5_SupportingPP1PVS1_Strong

This summary comes from the ClinGen Evidence Repository: The c.1137+1G>A (NM_004360.5) variant in CDH1 occurs within the canonical splice donor site (+/- 1,2) of intron 8. It is predicted to cause a frameshift leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1_strong, PM5_Supporitng). The highest population minor allele frequency in gnomAD v 2.1.1 is (0.00008) (2/24,962 alleles) in the African/African American population which is >1/50,000 alleles, thus, criterion is not met (PM2_Supporting). The variant has been reported to segregate with diffuse gastric cancer in 3 affected meioses from 1 family that fulfills the clinical HDGC criteria (PP1; PMIDs 10477433). This variant has been reported in 9 probands meeting hereditary diffuse gastric cancer criteria (PS4; PMIDs 26182300, 10477433, ClinVar SCVs SCV000288420.8, SCV000278454.7, Internal lab contributors). 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, PS3, PM5_Supporting and PP1. LINK:https://erepo.genome.network/evrepo/ui/classification/CA10580104/MONDO:0007648/007

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Consequence

CDH1
NM_004360.5 splice_donor

Scores

Splicing: ADA: 1.000

Clinical Significance

Pathogenic reviewed by expert panel P:7

Conservation

PhyloP100: 9.44

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PVS1

PS3

PS4

PM5

PP1

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	MANE
CDH1	NM_004360.5 linkuse as main transcript	c.1137+1G>A	splice_donor_variant	ENST00000261769.10
CDH1	NM_001317184.2 linkuse as main transcript	c.1137+1G>A	splice_donor_variant
CDH1	NM_001317185.2 linkuse as main transcript	c.-479+1G>A	splice_donor_variant
CDH1	NM_001317186.2 linkuse as main transcript	c.-683+1G>A	splice_donor_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDH1	ENST00000261769.10 linkuse as main transcript	c.1137+1G>A		splice_donor_variant		1	NM_004360.5	P1	P12830-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152200

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251452

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135898

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152200

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74348

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000113

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Hereditary diffuse gastric adenocarcinoma

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 20, 2017	Variant summary: The CDH1 c.1137+1G>A variant involves the alteration of a conserved intronic nucleotide and 5/5 splice prediction tools predict a significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. This variant was found in 2/277198 control chromosomes (gnomAD) at a frequency of 0.0000072, which does not exceed the estimated maximal expected allele frequency of a pathogenic CDH1 variant (0.0000283). Multiple publications have cited the variant in affected individuals including one family, which the variant segregates with disease (Guilford_1999). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Nov 18, 2023	This sequence change affects a donor splice site in intron 8 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 present in population databases (no rsID available, gnomAD 0.008%). Disruption of this splice site has been observed in individual(s) with diffuse gastric cancer (PMID: 10477433, 19725995). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 233979). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 26, 2018	This variant is denoted CDH1 c.1137+1G>A or IVS8+1G>A and consists of a G>A nucleotide substitution at the +1 position of intron 8 of the CDH1 gene. This variant destroys a canonical splice donor site and is predicted to cause abnormal gene splicing, leading to either an abnormal message that is subject to nonsense-mediated mRNA decay or to an abnormal protein product. This variant segregated in a kindred, with all four cases of diffuse gastric cancer (Guilford 1999). Based on the current evidence, we consider this variant to be pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Dec 19, 2017	- -

CDH1-related diffuse gastric and lobular breast cancer syndrome

Pathogenic:1

Pathogenic, reviewed by expert panel

curation

ClinGen CDH1 Variant Curation Expert Panel

Mar 25, 2024

The c.1137+1G>A (NM_004360.5) variant in CDH1 occurs within the canonical splice donor site (+/- 1,2) of intron 8. It is predicted to cause a frameshift leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1_strong, PM5_Supporitng). The highest population minor allele frequency in gnomAD v 2.1.1 is (0.00008) (2/24,962 alleles) in the African/African American population which is >1/50,000 alleles, thus, criterion is not met (PM2_Supporting). The variant has been reported to segregate with diffuse gastric cancer in 3 affected meioses from 1 family that fulfills the clinical HDGC criteria (PP1; PMIDs 10477433). This variant has been reported in 9 probands meeting hereditary diffuse gastric cancer criteria (PS4; PMIDs 26182300, 10477433, ClinVar SCVs SCV000288420.8, SCV000278454.7, Internal lab contributors). 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, PS3, PM5_Supporting and PP1. -

Hereditary cancer-predisposing syndrome

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 07, 2023

The c.1137+1G>A intronic pathogenic mutation results from a G to A substitution 1 nucleotide after coding exon 8 of the CDH1 gene. This alteration was previously described in a family meeting clinical diagnostic criteria for Hereditary Diffuse Gastric Cancer syndrome (HDGC), in which 4 individuals were diagnosed with diffuse gastric cancer between ages 25-58 (Guilford PJ et al. Hum. Mutat. 1999;14(3):249-55). Another alteration affecting the same splice donor site (CDH1 c.1137G>A) has been observed in multiple HDGC families (Lynch HT et al. Fam Cancer. 2011 Dec;10(4):667-72; More H et al. Hum Mutat. 2007 Feb;28(2):203; Kaurah P et al. JAMA 2007 Jun; 297(21):2360-72; Pantelis D et al. Int J Colorectal Dis, 2016 Dec;31:1825-1833) and has been shown to cause abnormal splicing (Karam R et al. Oncogene. 2008 Jul 10;27(30):4255-60). 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. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Familial cancer of breast

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Dec 15, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Uncertain

0.14

BayesDel_noAF

Pathogenic

0.14

CADD

Pathogenic

DANN

Uncertain

0.99

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

0.92

FATHMM_MKL

Pathogenic

0.99

MutationTaster

Benign

1.0

D;D

GERP RS

5.7

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.88

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over