rs587780789

Positions:

• chr16-68738332-C-A
• chr16-68738332-C-G
• chr16-68738332-C-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The ENST00000261769.10(CDH1):​c.84C>A​(p.Cys28Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. C28C) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000084 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000043 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CDH1 ENST00000261769.10 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: -0.0540

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 16 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 316 pathogenic variants in the truncated region.
• PP5: Variant 16-68738332-C-A is Pathogenic according to our data. Variant chr16-68738332-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 1763626.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CDH1	NM_004360.5	c.84C>A	p.Cys28Ter	stop_gained	2/16	ENST00000261769.10	NP_004351.1
CDH1	NM_001317184.2	c.84C>A	p.Cys28Ter	stop_gained	2/15		NP_001304113.1
CDH1	NM_001317185.2	c.-1532C>A		5_prime_UTR_variant	2/16		NP_001304114.1
CDH1	NM_001317186.2	c.-1736C>A		5_prime_UTR_variant	2/15		NP_001304115.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDH1	ENST00000261769.10	c.84C>A	p.Cys28Ter	stop_gained	2/16	1	NM_004360.5	ENSP00000261769	P1
CDH1	ENST00000422392.6	c.84C>A	p.Cys28Ter	stop_gained	2/15	1		ENSP00000414946
CDH1	ENST00000566612.5	c.84C>A	p.Cys28Ter	stop_gained, NMD_transcript_variant	2/15	1		ENSP00000454782
CDH1	ENST00000566510.5	c.84C>A	p.Cys28Ter	stop_gained, NMD_transcript_variant	2/15	5		ENSP00000458139

Frequencies

GnomAD3 genomes AF: 0.00 AC: 12 AN: 142366 Hom.: 0 Cov.: 32 FAILED QC

Gnomad AFR AF: 0.0000785

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000634

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000781

Gnomad OTH AF: 0.000534

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000431 AC: 6 AN: 1393722 Hom.: 0 Cov.: 31 AF XY: 0.00000727 AC XY: 5 AN XY: 687330

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000856

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000128

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000186

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000842 AC: 12 AN: 142482 Hom.: 0 Cov.: 32 AF XY: 0.0000430 AC XY: 3 AN XY: 69764

Gnomad4 AFR AF: 0.0000783

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000636

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000781

Gnomad4 OTH AF: 0.000529

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary diffuse gastric adenocarcinoma Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Myriad Genetics, Inc.

Jun 08, 2023

This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 22, 2024

The p.C28* pathogenic mutation (also known as c.84C>A), located in coding exon 2 of the CDH1 gene, results from a C to A substitution at nucleotide position 84. This changes the amino acid from a cysteine to a stop codon within coding exon 2. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.45
CADD	Pathogenic	32
DANN	Uncertain	0.99
Eigen	Uncertain	0.27
Eigen_PC	Benign	0.020
FATHMM_MKL	Benign	0.20	N
MutationTaster	Benign	1.0	A;A
Vest4		0.95
GERP RS		3.8

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs587780789; hg19: chr16-68772235;