NM_004360.5:c.2439+5_2439+8delGTAA

Variant names:

• chr16-68829795-GAAGT-G
• rs587782810
• NM_004360.5:c.2439+5_2439+8delGTAA

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PS3 PM2 PP3_Moderate PP5_Very_Strong

The NM_004360.5(CDH1):​c.2439+5_2439+8delGTAA variant causes a splice region, intron change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★★). ClinVar reports functional evidence for this variant: "SCV000187463: Internal RNA studies confirm that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data)." and additional evidence is available in ClinVar. The gene CDH1 is included in the ClinGen Criteria Specification Registry.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CDH1 NM_004360.5 splice_region, intron
• Clinical Significance: Likely pathogenic reviewed by expert panel P:3 U:1
• Conservation: PhyloP100: 9.82
• 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, Labcorp Genetics (formerly Invitae), G2P, Illumina
• CDH1-related diffuse gastric and lobular breast cancer syndrome

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

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

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics
• 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: Unknown Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Specifications for CDH1 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Pathogenic. The variant received 16 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000187463: Internal RNA studies confirm that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data).; SCV004812900: "This variant is predicted to affect splicing by SpliceAI and NNSPLICE (PP3). Additionally, there is an RNA assay demonstrating an abnormal out-of-frame transcript for this variant (PS3, internal laboratory contributors)."
• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 16-68829795-GAAGT-G is Pathogenic according to our data. Variant chr16-68829795-GAAGT-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 142905.Status of the report is reviewed_by_expert_panel, 3 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004360.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDH1	NM_004360.5	MANE Select	c.2439+5_2439+8delGTAA		splice_region intron	N/A	NP_004351.1	A0A0U2ZQU7
	CDH1	NM_001317184.2		c.2256+5_2256+8delGTAA		splice_region intron	N/A	NP_001304113.1	P12830-2
	CDH1	NM_001317185.2		c.891+5_891+8delGTAA		splice_region intron	N/A	NP_001304114.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDH1	ENST00000261769.10	TSL:1 MANE Select	c.2438_2439+2delAAGT	p.Asn814ValfsTer2	frameshift splice_donor splice_region intron	Exon 15 of 16	ENSP00000261769.4	P12830-1
	CDH1	ENST00000422392.6	TSL:1	c.2255_2256+2delAAGT	p.Asn753ValfsTer2	frameshift splice_donor splice_region intron	Exon 14 of 15	ENSP00000414946.2	P12830-2
	CDH1	ENST00000566612.5	TSL:1	n.*678_*679+2delAAGT		splice_region non_coding_transcript_exon	Exon 14 of 15	ENSP00000454782.1	H3BNC6

Frequencies

GnomAD3 genomes Cov.: 32

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

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
1	1	-	Hereditary diffuse gastric adenocarcinoma (2)
1	-	-	CDH1-related diffuse gastric and lobular breast cancer syndrome (1)
1	-	-	Hereditary cancer-predisposing syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		9.8
Mutation Taster		=2/198	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		1.0		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.45		Position offset: -50
DS_DL_spliceai		1.0		Position offset: 2

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs587782810; hg19: chr16-68863698;