rs587783050

Variant names:

• chr16-68812263-G-A
• rs587783050
• NM_004360.5:c.1137G>A

Your query was ambiguous. Multiple possible variants found:

• chr16-68812263-G-A
• chr16-68812263-G-C
• chr16-68812263-G-T

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PM2_Supporting PS3 PS4 PVS1_Moderate

This summary comes from the ClinGen Evidence Repository: The c.1137G>A p.(Thr379=) variant results in a G to non-G change at the last nucleotide of an exon (PVS1_Moderate). The variant is absent in the gnomAD cohort (PM2_Supporting; http://gnomad.broadinstitute.org). There is also an RNA assay demonstrating abnormal out-of-frame transcript (PS3; PMID:15831593). Additionally, this variant has been reported in at least 4 families meeting HDGC clinical criteria (PS4; PMID:15831593, 17545690, 17221870, 21681551, 27995193). In summary, this variant meets criteria to be classified as pathogenic based on the ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): PVS1_Moderate, PM2_Supporting, PS3, PS4. LINK:https://erepo.genome.network/evrepo/ui/classification/CA186229/MONDO:0007648/007

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: CDH1 NM_004360.5 splice_region, synonymous
• Scores: Splicing: ADA: 0.9998
• Clinical Significance: Pathogenic reviewed by expert panel P:17 O:1
• Conservation: PhyloP100: 2.78
• Publications: 27 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: Pathogenic. The variant received 11 ACMG points.

• PVS1: For more information check the summary or visit ClinGen Evidence Repository.
• PS3: For more information check the summary or visit ClinGen Evidence Repository.
• PS4: For more information check the summary or visit ClinGen Evidence Repository.
• PM2: 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.1137G>A	p.Thr379Thr	splice_region_variant, synonymous_variant	Exon 8 of 16	ENST00000261769.10	NP_004351.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDH1	ENST00000261769.10	c.1137G>A	p.Thr379Thr	splice_region_variant, synonymous_variant	Exon 8 of 16	1	NM_004360.5	ENSP00000261769.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461676 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727152

African (AFR) AF: 0.00 AC: 0 AN: 33472

American (AMR) AF: 0.00 AC: 0 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86220

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53400

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111886

Other (OTH) AF: 0.00 AC: 0 AN: 60386

GnomAD4 genome Cov.: 32

Alfa AF: 0.00000497 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:17 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Hereditary diffuse gastric adenocarcinoma Pathogenic:8 Other:1

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: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PVS1_Moderate; PS3; PS4; PM2 (PMID: 30311375) -

Jul 11, 2021

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: CDH1 c.1137G>A (p.Thr379Thr) alters a conserved nucleotide located as the last nucleotide of exon 8 adjacent to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Two predict the variant abolishes the canonical 5' splicing donor site. Two predict the variant weakens the canonical 5' donor site. At least one publication reports experimental evidence that this variant affects mRNA splicing resulting in a complex aberant pattern of alternatively spliced transcripts (example, Frebourg_2006). The variant was absent in 251452 control chromosomes. c.1137G>A has been reported in the literature in multiple individuals from families affected with Hereditary Diffuse Gastric Cancer (example, Frebourg_2006, Kaurah_2007, More_2007, Niemeyer_2020). These data indicate that the variant is very likely to be associated with disease. Multiple clinical diagnostic laboratories and one expert panel (ClinGen CDH1 Variant Curation Expert Panel) have submitted clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic (n=6 to include the expert panel)/likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as pathogenic. -

Jul 24, 2014

Pathway Genomics

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Aug 23, 2021

MGZ Medical Genetics Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 22, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change affects codon 379 of the CDH1 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the CDH1 protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or altered protein product. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individuals with clinical features of hereditary diffuse gastric cancer (PMID: 15831593, 17221870, 17545690, 19725995, 21681551, 23709761, 26025002, 27682646; internal data). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 156499). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in aberrant splicing, leading to expression of several defective alternate splicing products and high levels of allelic expression imbalance of the CDH1 gene, and produces a non-functional protein and/or introduces a premature termination codon (PMID: 15831593, 18427545, 19965908). For these reasons, this variant has been classified as Pathogenic. -

Mar 06, 2023

Myriad Genetics, Inc.

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely pathogenic. mRNA analysis has demonstrated abnormal mRNA splicing occurs [Myriad internal data,17726045, 15831593]. This variant has been reported in multiple individuals with clinical features of gene-specific disease [17545690, 17221870, 21681551]. -

-

GenomeConnect, ClinGen

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

Variant interpreted as Pathogenic and reported on 08-12-2019 by Lab or GTR ID 1197. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -

Jul 19, 2016

Counsyl

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

May 16, 2023

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Criteria applied: PVS1,PS4,PS1_SUP,PM2_SUP, PS3 -

not provided Pathogenic:3

Mar 24, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant at the last nucleotide of an exon predicted to result in a null allele in a gene for which loss-of-function is a known mechanism of disease (Frebourg et al., 2006; Karam et al., 2008); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 26025002, 19965908, 17221870, 19725995, 21681551, 15831593, 21271559, 28117042, 27682646, 28281021, 22225527, 20373070, 19269290, 29468433, 17545690, 23709761, 26182300, 30311375, 32362280, 30426508, 34949788, 30745422, 31514334, 27995193, 18427545) -

Dec 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

CDH1: PS4, PM2, PVS1:Moderate, PP1, PS3:Supporting -

Feb 25, 2015

Clinical Genetics and Genomics, Karolinska University Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Pathogenic:2

Feb 17, 2023

Color Diagnostics, LLC DBA Color Health

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant causes a G>A nucleotide substitution at the last nucleotide of exon 8 of the CDH1 gene. Splice site prediction tools suggest that this variant may impact RNA splicing. Functional RNA studies using patient-derived cells have shown that this variant causes a complex aberrant splicing affecting exon 8 (PMID: 15831593, 18427545, 19965908). This variant has been reported in multiple individuals affected with diffuse gastric cancer (PMID: 15831593, 17221870, 17545690, 21271559, 21681551, 23709761, 27682646, 32362280) and lobular breast cancer (PMID: 30426508). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. -

Jul 14, 2022

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1137G>A mutation (also known as p.T379T) is located in coding exon 8 of the CDH1 gene. This mutation results from a G to A substitution at nucleotide position 1137. This alteration occurs in the last nucleotide of coding exon 8, adjacent to the canonical splice donor site, and leads to the generation of an alternately spliced transcript harboring a premature stop codon (Karam R et al. Oncogene. 2008 Jul;27:4255-60; Ambry internal data). This mutation has been observed in multiple HDGC families (Lynch HT et al. Fam Cancer. 2011 Dec;10:667-72; More H et al. Hum. Mutat. 2007 Feb;28:203; Kaurah P et al. JAMA. 2007 Jun;297:2360-72; Pantelis D et al. Int J Colorectal Dis. 2016 Dec;31:1825-1833), including one family where this mutation segregated with disease through two generations and was also found in three family members with both gastric cancer and cleft lip and palate, and another family member with gastric cancer and cleft lip (Frebourg T et al. J. Med. Genet. 2006 Feb;43:138-42). It was also seen in a patient with invasive ductal triple negative breast cancer and in her aunt with bilateral lobular breast cancer (Schubert S et al. Int. J. Cancer. 2019 Jun;144(11):2683-2694). Based on the available evidence to date, this alteration is classified as a pathogenic mutation. -

Familial cancer of breast;C1140680:Ovarian cancer Pathogenic:1

Dec 21, 2020

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Diffuse gastric and lobular breast cancer syndrome with cleft lip and with or without cleft palate Pathogenic:1

Feb 01, 2006

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

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

Aug 29, 2023

ClinGen CDH1 Variant Curation Expert Panel

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: curation

The c.1137G>A p.(Thr379=) variant results in a G to non-G change at the last nucleotide of an exon (PVS1_Moderate). The variant is absent in the gnomAD cohort (PM2_Supporting; http://gnomad.broadinstitute.org). There is also an RNA assay demonstrating abnormal out-of-frame transcript (PS3; PMID: 15831593). Additionally, this variant has been reported in at least 4 families meeting HDGC clinical criteria (PS4; PMID: 15831593, 17545690, 17221870, 21681551, 27995193). In summary, this variant meets criteria to be classified as pathogenic based on the ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): PVS1_Moderate, PM2_Supporting, PS3, PS4. -

Familial cancer of breast Pathogenic:1

Dec 09, 2022

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

PS4_STR, PS3, PM2_SUP, PP1 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.70
CADD	Benign	22
DANN	Benign	0.64
PhyloP100		2.8
Mutation Taster		=23/77	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.98
Splicevardb		3.0
SpliceAI score (max)		0.33		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.33		Position offset: 0

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

Other links and lift over

dbSNP: rs587783050; hg19: chr16-68846166; COSMIC: COSV55733400; COSMIC: COSV55733400;