rs786201115

Variant names:

• chr16-68738368-G-A
• rs786201115
• NM_004360.5:c.120G>A

Your query was ambiguous. Multiple possible variants found:

• chr16-68738368-G-A
• chr16-68738368-G-C
• chr16-68738368-G-T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 1P and 3B. PM2_Supporting BP4 BS2_Supporting BP7

This summary comes from the ClinGen Evidence Repository: The c.120G>A (p.Thr40=) variant results in a synonymous amino acid change in exon 2. Although this variant is absent from gnomAD (PM2_Supporting), it has been observed internally in at least three individuals without DGC, SRC tumours or LBC and whose families do not suggest HDGC (BS2_Supporting, SCV000214188.4, SCV001041247.2). In addition, this variant is not predicted to result in aberrant splicing and is not highly conserved (BP4, BP7). In summary, this variant meets criteria to be classified as likely benign based on the ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): BS2_supporting, BP4, BP7, PM2_Supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA188783/MONDO:0007648/007

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CDH1 NM_004360.5 synonymous
• Clinical Significance: Likely benign reviewed by expert panel B:6
• Conservation: PhyloP100: -2.33
• Publications: 1 publications found

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 Gene-Disease associations (from GenCC):

• blepharocheilodontic syndrome 1

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, Illumina, Labcorp Genetics (formerly Invitae), G2P
• CDH1-related diffuse gastric and lobular breast cancer syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, G2P
• hereditary breast carcinoma

  Inheritance: AD Classification: DEFINITIVE Submitted by: Ambry Genetics
• hereditary diffuse gastric adenocarcinoma

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet
• cleft soft palate

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
• orofacial cleft 3

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
• blepharocheilodontic syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• familial ovarian cancer

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Likely_benign. The variant received -2 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 rank	MANE	Protein	UniProt
CDH1	NM_004360.5	c.120G>A	p.Thr40Thr	synonymous_variant	Exon 2 of 16	ENST00000261769.10	NP_004351.1
CDH1	NM_001317184.2	c.120G>A	p.Thr40Thr	synonymous_variant	Exon 2 of 15		NP_001304113.1
CDH1	NM_001317185.2	c.-1496G>A		5_prime_UTR_variant	Exon 2 of 16		NP_001304114.1
CDH1	NM_001317186.2	c.-1700G>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.120G>A	p.Thr40Thr	synonymous_variant	Exon 2 of 16	1	NM_004360.5	ENSP00000261769.4
CDH1	ENST00000422392.6	c.120G>A	p.Thr40Thr	synonymous_variant	Exon 2 of 15	1		ENSP00000414946.2
CDH1	ENST00000566612.5	n.120G>A		non_coding_transcript_exon_variant	Exon 2 of 15	1		ENSP00000454782.1
CDH1	ENST00000566510.5	n.120G>A		non_coding_transcript_exon_variant	Exon 2 of 15	5		ENSP00000458139.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1398764 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 689906

African (AFR) AF: 0.00 AC: 0 AN: 31584

American (AMR) AF: 0.00 AC: 0 AN: 35678

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25156

East Asian (EAS) AF: 0.00 AC: 0 AN: 35770

South Asian (SAS) AF: 0.00 AC: 0 AN: 79176

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49018

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5698

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1078704

Other (OTH) AF: 0.00 AC: 0 AN: 57980

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely benign

Submissions summary: Benign:6

Revision: reviewed by expert panel

Submissions by phenotype

Hereditary diffuse gastric adenocarcinoma Benign:2

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 04, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Benign:2

Jul 25, 2017

Color Diagnostics, LLC DBA Color Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 23, 2018

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. -

not specified Benign:1

Aug 28, 2019

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 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.120G>A (p.Thr40=) variant results in a synonymous amino acid change in exon 2. Although this variant is absent from gnomAD (PM2_Supporting), it has been observed internally in at least three individuals without DGC, SRC tumours or LBC and whose families do not suggest HDGC (BS2_Supporting, SCV000214188.4, SCV001041247.2). In addition, this variant is not predicted to result in aberrant splicing and is not highly conserved (BP4, BP7). In summary, this variant meets criteria to be classified as likely benign based on the ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): BS2_supporting, BP4, BP7, PM2_Supporting. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.70
CADD	Benign	2.4
DANN	Benign	0.93
PhyloP100		-2.3

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

Other links and lift over

dbSNP: rs786201115; hg19: chr16-68772271;