rs786202657

Variant names:

• chr16-68738317-G-A
• rs786202657
• NM_004360.5:c.69G>A

Your query was ambiguous. Multiple possible variants found:

• chr16-68738317-G-A
• chr16-68738317-G-C

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 1P and 2B. PM2_Supporting BP7 BS2_Supporting

This summary comes from the ClinGen Evidence Repository: The c.69G>A (p.Glu23=) variant is absent from the gnomAD cohort (PM2_Supporting; https://gnomad.broadinstitute.org). In silico splice site predictors do not suggest that this variant impacts splicing, and the G allele is not highly conserved across species (BP7).The variant has also been observed in >3 individuals without a diagnosis of diffuse gastric cancer, signet ring tumor or lobular breast cancer and whose family histories do not suggest HDGC (BS2_Supporting; SCV000216307.4, SCV000545385.4, internal laboratory). Use of the Bayesian point system for this variant with conflicting evidence and classify this variant as likely benign. In summary, this variant meets criteria to be classified as likely benign based on ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): PM2_Supporting, BP7, BS2_Supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA193735/MONDO:0007648/007

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000036 (0 hom.)
• Consequence: CDH1 NM_004360.5 synonymous
• Clinical Significance: Likely benign reviewed by expert panel U:1 B:8
• Conservation: PhyloP100: 1.18

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_benign. Variant got -1 ACMG points.

• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• BP7: For more information check the summary or visit ClinGen Evidence Repository.
• BS2: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDH1	NM_004360.5	c.69G>A	p.Gln23Gln	synonymous_variant	Exon 2 of 16	ENST00000261769.10	NP_004351.1
CDH1	NM_001317184.2	c.69G>A	p.Gln23Gln	synonymous_variant	Exon 2 of 15		NP_001304113.1
CDH1	NM_001317185.2	c.-1547G>A		5_prime_UTR_variant	Exon 2 of 16		NP_001304114.1
CDH1	NM_001317186.2	c.-1751G>A		5_prime_UTR_variant	Exon 2 of 15		NP_001304115.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDH1	ENST00000261769.10	c.69G>A	p.Gln23Gln	synonymous_variant	Exon 2 of 16	1	NM_004360.5	ENSP00000261769.4
CDH1	ENST00000422392.6	c.69G>A	p.Gln23Gln	synonymous_variant	Exon 2 of 15	1		ENSP00000414946.2
CDH1	ENST00000566612.5	n.69G>A		non_coding_transcript_exon_variant	Exon 2 of 15	1		ENSP00000454782.1
CDH1	ENST00000566510.5	n.69G>A		non_coding_transcript_exon_variant	Exon 2 of 15	5		ENSP00000458139.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000357 AC: 5 AN: 1398762 Hom.: 0 Cov.: 31 AF XY: 0.00000580 AC XY: 4 AN XY: 689918

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000464

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:1 Benign:8

Revision: reviewed by expert panel

Submissions by phenotype

Hereditary diffuse gastric adenocarcinoma Benign:3

Sep 11, 2024

Myriad Genetics, Inc.

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered benign. This variant is a silent/synonymous amino acid change and it is not expected to impact splicing. -

Aug 01, 2022

European Reference Network on Genetic Tumour Risk Syndromes (ERN-GENTURIS), i3s - Instituto de Investigação e Inovação em Saúde, University of Porto

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM2; BS2_Supporting; BP7 (PMID: 30311375) -

Jan 25, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Benign:2

Aug 14, 2014

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Jan 10, 2017

Color Diagnostics, LLC DBA Color Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Uncertain:1

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The CDH1 p.Gln23= variant was identified in 1 of 808 proband chromosomes (frequency: 0.001) from individuals with a neurodevelopmental disorder (Kraemer 2019). The variant was identified in dbSNP (rs786202657) as “with uncertain significance allele” and ClinVar (classified as likely benign by Color and Ambry Genetics and uncertain significance by Invitae). The variant was not identified in the following control databases: the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). The p.Gln23= variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. The variant occurs at a non-highly conserved nucleotide outside of the splicing consensus sequence and 4 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing. However, this information is not predictive enough to assume pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -

not specified Benign:1

Oct 21, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

CDH1-related disorder Benign:1

Aug 29, 2024

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

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

Aug 18, 2023

ClinGen CDH1 Variant Curation Expert Panel

Significance: Likely benign

Review Status: reviewed by expert panel

Collection Method: curation

The c.69G>A (p.Glu23=) variant is absent from the gnomAD cohort (PM2_Supporting; https://gnomad.broadinstitute.org). In silico splice site predictors do not suggest that this variant impacts splicing, and the G allele is not highly conserved across species (BP7).The variant has also been observed in >3 individuals without a diagnosis of diffuse gastric cancer, signet ring tumor or lobular breast cancer and whose family histories do not suggest HDGC (BS2_Supporting; SCV000216307.4, SCV000545385.4, internal laboratory). Use of the Bayesian point system for this variant with conflicting evidence and classify this variant as likely benign. In summary, this variant meets criteria to be classified as likely benign based on ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): PM2_Supporting, BP7, BS2_Supporting. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.63
CADD	Benign	7.4
DANN	Benign	0.89
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs786202657; hg19: chr16-68772220;