chr16-68801776-G-A

Position:

chr16-68801776-G-A

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. BS2PM2_SupportingBP4BP7

This summary comes from the ClinGen Evidence Repository: The c.270G>A variant (NM_004360.5) is a synonymous (silent) variant (p.Arg90=) that is not predicted by SpliceAI, varSEAK to impact splicing (BP4, BP7). This variant has been observed in more than 10 heterozygous individuals with no GC, DGC, SRC tumors and whose families do not suggest HDGC (BS2; Invitae, Ambry, GeneDX). The variant is 1 out of 251,334 alleles (less than 1 out of 100,000) in gnomAD 2.1.1 cohort (PM2_Supporting). In summary, this variant meets criteria to be classified as likely benign for DGLBCS based on ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel: BS2, BP4, BP7, PM2_Supporting. The CDH1 VCEP classified the variant with conflicting criteria to likely benign based on Bayesian points calculation. (CDH1 VCEP specifications version 3.1; 05/06/2022) LINK:https://erepo.genome.network/evrepo/ui/classification/CA8129820/MONDO:0100488/007

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000075 ( 0 hom. )

Consequence

CDH1
NM_004360.5 synonymous

Scores

Clinical Significance

Likely benign reviewed by expert panel B:7

Conservation

PhyloP100: -2.06

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 Likely_benign. Variant got -5 ACMG points.

PM2

For more information check the summary or visit ClinGen Evidence Repository.

BP4

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/exons	MANE	Protein
CDH1	NM_004360.5 linkuse as main transcript	c.270G>A	p.Arg90=	synonymous_variant	3/16	ENST00000261769.10	NP_004351.1
CDH1	NM_001317184.2 linkuse as main transcript	c.270G>A	p.Arg90=	synonymous_variant	3/15		NP_001304113.1
CDH1	NM_001317185.2 linkuse as main transcript	c.-1346G>A		5_prime_UTR_variant	3/16		NP_001304114.1
CDH1	NM_001317186.2 linkuse as main transcript	c.-1550G>A		5_prime_UTR_variant	3/15		NP_001304115.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDH1	ENST00000261769.10 linkuse as main transcript	c.270G>A	p.Arg90=	synonymous_variant	3/16	1	NM_004360.5	ENSP00000261769	P1	P12830-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251334

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135838

show subpopulations

Gnomad AFR exome

AF:

0.00

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:

0.000163

GnomAD4 exome

AF:

0.00000752

AC:

AN:

1461868

Hom.:

Cov.:

AF XY:

0.00000688

AC XY:

AN XY:

727236

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000434

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Likely benign

Submissions summary: Benign:7

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Nov 15, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 20, 2015	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. -
Likely benign, criteria provided, single submitter	curation	Sema4, Sema4	Jan 23, 2022	- -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

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

Aug 28, 2019

- -

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 07, 2018

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Hereditary diffuse gastric adenocarcinoma

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 18, 2023

- -

CDH1-related diffuse gastric and lobular breast cancer syndrome

Benign:1

Likely benign, reviewed by expert panel

curation

ClinGen CDH1 Variant Curation Expert Panel

Aug 02, 2023

The c.270G>A variant (NM_004360.5) is a synonymous (silent) variant (p.Arg90=) that is not predicted by SpliceAI, varSEAK to impact splicing (BP4, BP7). This variant has been observed in more than 10 heterozygous individuals with no GC, DGC, SRC tumors and whose families do not suggest HDGC (BS2; Invitae, Ambry, GeneDX). The variant is 1 out of 251,334 alleles (less than 1 out of 100,000) in gnomAD 2.1.1 cohort (PM2_Supporting). In summary, this variant meets criteria to be classified as likely benign for DGLBCS based on ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel: BS2, BP4, BP7, PM2_Supporting. The CDH1 VCEP classified the variant with conflicting criteria to likely benign based on Bayesian points calculation. (CDH1 VCEP specifications version 3.1; 05/06/2022) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.86

CADD

Benign

0.090

DANN

Benign

0.42

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

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