16-68833355-T-G

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PVS1_Strong PM2 PP3 PP5_Very_Strong

The NM_004360.5(CDH1):c.2505T>G(p.Tyr835Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★★). Synonymous variant affecting the same amino acid position (i.e. Y835Y) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CDH1 NM_004360.5 stop_gained
• Clinical Significance: Likely pathogenic reviewed by expert panel P:1 U:1
• Conservation: PhyloP100: -1.24

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 Pathogenic. Variant got 15 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 5 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 16-68833355-T-G is Pathogenic according to our data. Variant chr16-68833355-T-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 921477.Status of the report is reviewed_by_expert_panel, 3 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDH1	NM_004360.5	c.2505T>G	p.Tyr835Ter	stop_gained	16/16	ENST00000261769.10
CDH1	NM_001317184.2	c.2322T>G	p.Tyr774Ter	stop_gained	15/15
CDH1	NM_001317185.2	c.957T>G	p.Tyr319Ter	stop_gained	16/16
CDH1	NM_001317186.2	c.540T>G	p.Tyr180Ter	stop_gained	15/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDH1	ENST00000261769.10	c.2505T>G	p.Tyr835Ter	stop_gained	16/16	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:1 Uncertain:1

Revision: reviewed by expert panel

Submissions by phenotype

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.2505T>G (p.Tyr835Ter) variant results in a premature translational stop signal upstream of the most 3' well-characterized pathogenic variant c.2506G>T (p.Glu836Ter) in a region that is not predicted to undergo nonsense-mediated decay (PVS1_Strong, PM5_Supporting). It is absent in the gnomAD cohort (PM2_Supporting; http://https://gnomad.broadinstitute.org/). In summary, 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: PVS1_Strong, PM2_Supporting, PM5_Supporting. (CDH1 VCEP specifications version 3.1; 03/27/2023) -

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Feb 22, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.58
Cadd	Pathogenic	35
Dann	Uncertain	0.99
Eigen	Benign	0.038
Eigen_PC	Benign	-0.23
FATHMM_MKL	Benign	0.39	N
MutationTaster	Benign	1.0	D;D
Vest4		0.85
GERP RS		-3.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.76		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.76		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: rs786202613; hg19: chr16-68867258;