chr16-68811859-G-T

Position:

• chr16-68811859-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PS4_Supporting PM2_Supporting PS3 PVS1_Moderate

This summary comes from the ClinGen Evidence Repository: The c.1008G>T (p.Glu336Asp) variant results in a G to non-G change at the last nucleotide of an exon (PVS1_Moderate). This variant is absent in the gnomAD cohort (PM2_Supporting; http://gnomad.broadinstitute.org). There is an RNA assay demonstrating an abnormal out-of-frame transcript for this variant (PS3; PMID:9537325). Additionally, the variant has also been reported in at least one family meeting HDGC clinical criteria (PS4_Supporting; PMID:9537325). 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_Moderate, PM2_Supporting, PS3, PS4_Supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA280990/MONDO:0007648/007

• Frequency: Genomes: not found (cov: 32)
• Consequence: CDH1 NM_004360.5 missense, splice_region
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Likely pathogenic reviewed by expert panel P:4
• Conservation: PhyloP100: 9.60

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 8 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CDH1	NM_004360.5	c.1008G>T	p.Glu336Asp	missense_variant, splice_region_variant	7/16	ENST00000261769.10	NP_004351.1
CDH1	NM_001317184.2	c.1008G>T	p.Glu336Asp	missense_variant, splice_region_variant	7/15		NP_001304113.1
CDH1	NM_001317185.2	c.-608G>T		splice_region_variant, 5_prime_UTR_variant	7/16		NP_001304114.1
CDH1	NM_001317186.2	c.-812G>T		splice_region_variant, 5_prime_UTR_variant	7/15		NP_001304115.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDH1	ENST00000261769.10	c.1008G>T	p.Glu336Asp	missense_variant, splice_region_variant	7/16	1	NM_004360.5	ENSP00000261769	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

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jan 23, 2024

Not observed at significant frequency in large population cohorts (gnomAD); Alters the last nucleotide of the exon and is predicted to destroy the splice donor site and result in aberrant splicing; Identified in several individuals with diffuse gastric cancer, and reported to segregate with disease in affected kindreds (PMID: 19223545, 26182300, 9537325, 31642931); This variant is associated with the following publications: (PMID: 25525159, 8127895, 28460635, 35882702, 23709761, 30311375, 32963463, 15235021, 22850631, 31642931, 30745422, 9537325, 36063148, 29468433, 19725995, 25184143, 30661051, 26182300, 15138207, 15753528, 9744472, 19223545, 30547291) -

DIFFUSE GASTRIC AND LOBULAR BREAST CANCER SYNDROME Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Mar 26, 1998

- -

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 28, 2023

The c.1008G>T (p.Glu336Asp) variant results in a G to non-G change at the last nucleotide of an exon (PVS1_Moderate). This variant is absent in the gnomAD cohort (PM2_Supporting; http://gnomad.broadinstitute.org). There is an RNA assay demonstrating an abnormal out-of-frame transcript for this variant (PS3; PMID: 9537325). Additionally, the variant has also been reported in at least one family meeting HDGC clinical criteria (PS4_Supporting; PMID: 9537325). 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_Moderate, PM2_Supporting, PS3, PS4_Supporting. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 18, 2024

The c.1008G>T pathogenic mutation (also known as p.E336D), located in coding exon 7 of the CDH1 gene, results from a G to T substitution at nucleotide position 1008. This change occurs in the last base pair of coding exon 7, which makes it likely to have some effect on normal mRNA splicing. In addition to potential splicing impact, this alteration changes the glutamic acid at codon 336 to aspartic acid, an amino acid with highly similar properties. This alteration segregated with disease in a family with hereditary diffuse gastric cancer, and RT-PCR studies demonstrated a 7 base pair insertion between the normal splice donor site and an adjacent cryptic splice site (Guilford P et al. Nature 1998 Mar;392:402-5). Internal RNA splicing analyses confirmed this out-of-frame 7 base pair insertion and showed additional out-of-frame transcripts containing a 25 base pair insertion and an insertion of intron 7 (Ambry internal data). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.18
CADD	Pathogenic	35
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.53	D;T;T;.;.
Eigen	Pathogenic	0.97
Eigen_PC	Pathogenic	0.92
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.91	D;D;D;D;D
M_CAP	Uncertain	0.10	D
MetaRNN	Pathogenic	0.75	D;D;D;D;D
MetaSVM	Uncertain	0.38	D
MutationAssessor	Uncertain	2.6	M;.;.;.;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.59	T
PROVEAN	Uncertain	-2.9	D;.;.;.;D
REVEL	Uncertain	0.63
Sift	Uncertain	0.0020	D;.;.;.;T
Sift4G	Uncertain	0.0050	D;D;D;D;D
Polyphen		1.0	D;.;.;.;.
Vest4		0.84
MutPred		0.28		Gain of sheet (P = 0.1539);Gain of sheet (P = 0.1539);Gain of sheet (P = 0.1539);Gain of sheet (P = 0.1539);Gain of sheet (P = 0.1539);
MVP		0.95
MPC		0.84
ClinPred		0.99	D
GERP RS		5.5
Varity_R		0.93
gMVP		0.70

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	1.0
SpliceAI score (max)		0.91		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.20		Position offset: 7
DS_DL_spliceai		0.91		Position offset: 0

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

Publications

LitVar

Other links and lift over

dbSNP: rs267606712; hg19: chr16-68845762;