rs1060501224

Positions:

• chr16-68822179-AAC-A

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PS4_Moderate PM5_Supporting PVS1 PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The c.1895_1896delAC (p.His632ArgfsTer30) variant is predicted to result in a premature stop codon that leads to a truncated or absent protein (PVS1, PM5_Supporting). The variant is absent in the gnomAD cohort (PM2_Supporting; http://gnomad.broadinstitute.org). This variant has been reported in at least two familes meeting HDGC clinical criteria (PS4_Moderate; PMID 26182300, https://doi.org/10.2147/GICTT.S16330). 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, PM2_Supporting, PS4_Moderate, PM5_Supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CV406628/MONDO:0007648/007

• Frequency: Genomes: not found (cov: 31)
• Consequence: CDH1 NM_004360.5 frameshift
• Clinical Significance: Pathogenic reviewed by expert panel P:6
• Conservation: PhyloP100: 0.822

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 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PVS1: 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.
• PM5: 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.1895_1896delAC	p.His632fs	frameshift_variant	12/16	ENST00000261769.10	NP_004351.1
CDH1	NM_001317184.2	c.1712_1713delAC	p.His571fs	frameshift_variant	11/15		NP_001304113.1
CDH1	NM_001317185.2	c.347_348delAC	p.His116fs	frameshift_variant	12/16		NP_001304114.1
CDH1	NM_001317186.2	c.-71_-70delAC		5_prime_UTR_variant	11/15		NP_001304115.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDH1	ENST00000261769.10	c.1895_1896delAC	p.His632fs	frameshift_variant	12/16	1	NM_004360.5	ENSP00000261769.4

Frequencies

GnomAD3 genomes Cov.: 31

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: reviewed by expert panel

Submissions by phenotype

Hereditary diffuse gastric adenocarcinoma Pathogenic:4

Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Mar 24, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 26, 2020	For these reasons, this variant has been classified as Pathogenic. While this particular variant has not been reported in the literature, truncating variants in CDH1 are known to be pathogenic (PMID: 15235021, 20373070). This sequence change deletes 2 nucleotides from exon 12 of the CDH1 mRNA (c.1895_1896delAC), causing a frameshift at codon 632. This creates a premature translational stop signal (p.His632Argfs*30) and is expected to result in an absent or disrupted protein product. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 09, 2016	Variant summary: The CDH1 c.1895_1896delAC (p.His632Argfs) variant results in a premature termination codon, predicted to cause a truncated or absent CDH1 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. One in silico tool predicts a damaging outcome for this variant. This variant is absent in 12988 control chromosomes. This variant has been reported in multiple families with strong fx of GC. One of the families showed partial co-segregation of variant with diease, suggesting this variant may be of low penetrance. HDGC is known to be an uncommon hereditary form of GC with variable penetrance, 67% for men and 83% for women (Shenoy_2011). The variant of interest has not, to our knowledge, been reported in affected individuals via reputable databases/clinical diagnostic laboratories; evaluated for functional impact by in vivo/vitro studies. Taken together, this variant is classified as likely pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Mar 03, 2023	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation. -

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

Pathogenic, reviewed by expert panel

curation

ClinGen CDH1 Variant Curation Expert Panel

Aug 25, 2023

The c.1895_1896delAC (p.His632ArgfsTer30) variant is predicted to result in a premature stop codon that leads to a truncated or absent protein (PVS1, PM5_Supporting). The variant is absent in the gnomAD cohort (PM2_Supporting; http://gnomad.broadinstitute.org). This variant has been reported in at least two familes meeting HDGC clinical criteria (PS4_Moderate; PMID 26182300, https://doi.org/10.2147/GICTT.S16330). 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, PM2_Supporting, PS4_Moderate, PM5_Supporting. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 04, 2021

The c.1895_1896delAC pathogenic mutation, located in coding exon 12 of the CDH1 gene, results from a deletion of two nucleotides at nucleotide positions 1895 to 1896, causing a translational frameshift with a predicted alternate stop codon (p.H632Rfs*30). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs1060501224; hg19: chr16-68856082;