chr16-68815760-G-GTT

Variant names:

• chr16-68815760-G-GTT
• rs1555516200
• NM_004360.5:c.1565+2_1565+3insTT

Variant summary

Our verdict is Pathogenic. The variant received 22 ACMG points: 22P and 0B. PVS1 PS3 PM2 PP5_Very_Strong

The ENST00000261769.10(CDH1):​c.1565+1_1565+2insTT variant causes a splice donor, intron change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000637733: Studies have shown that this variant alters mRNA splicing and is expected to lead to the loss of protein expression (PMID:24389957).; SCV000675991: Bardram et al. further assessed the functional significance of this alteration using a mini-gene assay and showed this alteration results in a deletion of exon 10. Authors also note that seven asymptomatic mutation carriers underwent prophylactic gastrectomy and small foci of diffuse gastric cancer were found in all patients. PMID:24896178; SCV000903634: "This variant resulted in two aberrant splicing products predicted to create absent or non-functional protein product" (PMID:24389957).".

• Frequency: Genomes: not found (cov: 32)
• Consequence: CDH1 ENST00000261769.10 splice_donor, intron
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 7.46
• Publications: 2 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

ENSG00000260798 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 22 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.
• PS3: PS3 evidence extracted from ClinVar submissions: SCV000637733: Studies have shown that this variant alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 24389957).; SCV000675991: Bardram et al. further assessed the functional significance of this alteration using a mini-gene assay and showed this alteration results in a deletion of exon 10. Authors also note that seven asymptomatic mutation carriers underwent prophylactic gastrectomy and small foci of diffuse gastric cancer were found in all patients. PMID:24896178; SCV000903634: "This variant resulted in two aberrant splicing products predicted to create absent or non-functional protein product" (PMID: 24389957).
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 16-68815760-G-GTT is Pathogenic according to our data. Variant chr16-68815760-G-GTT is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 463722.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000261769.10. 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.1565+2_1565+3insTT		splice_region intron	N/A	NP_004351.1	A0A0U2ZQU7
	CDH1	NM_001317184.2		c.1382+2_1382+3insTT		splice_region intron	N/A	NP_001304113.1	P12830-2
	CDH1	NM_001317185.2		c.17+2_17+3insTT		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.1565+1_1565+2insTT		splice_donor intron	N/A	ENSP00000261769.4	P12830-1
	CDH1	ENST00000422392.6	TSL:1	c.1382+1_1382+2insTT		splice_donor intron	N/A	ENSP00000414946.2	P12830-2
	CDH1	ENST00000562836.5	TSL:1	n.1636+1_1636+2insTT		splice_donor intron	N/A

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
3	-	-	Hereditary cancer-predisposing syndrome (3)
2	-	-	not provided (2)
1	-	-	CDH1-related diffuse gastric and lobular breast cancer syndrome (1)
1	-	-	Hereditary diffuse gastric adenocarcinoma (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.5
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

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

Other links and lift over

dbSNP: rs1555516200; hg19: chr16-68849663;