rs777822181

Positions:

• chr16-68801776-G-A
• chr16-68801776-G-C
• chr16-68801776-G-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. BS2 PM2_Supporting BP4 BP7

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
• Clinical Significance: Likely benign reviewed by expert panel B:7
• Conservation: PhyloP100: -2.06

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 -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	UniProt
CDH1	NM_004360.5	c.270G>A	p.Arg90=	synonymous_variant	3/16	ENST00000261769.10	NP_004351.1
CDH1	NM_001317184.2	c.270G>A	p.Arg90=	synonymous_variant	3/15		NP_001304113.1
CDH1	NM_001317185.2	c.-1346G>A		5_prime_UTR_variant	3/16		NP_001304114.1
CDH1	NM_001317186.2	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	c.270G>A	p.Arg90=	synonymous_variant	3/16	1	NM_004360.5	ENSP00000261769	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251334 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135838

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: 11 AN: 1461868 Hom.: 0 Cov.: 32 AF XY: 0.00000688 AC XY: 5 AN XY: 727236

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.: 32

Alfa AF: 0.0000434 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Likely benign

Submissions summary: Benign:7

Revision: reviewed by expert panel

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

Other links and lift over

dbSNP: rs777822181; hg19: chr16-68835679;