rs1131690818

Variant names:

• chr16-68819430-G-A
• rs1131690818
• NM_004360.5:c.1711+5G>A

Your query was ambiguous. Multiple possible variants found:

• chr16-68819430-G-A
• chr16-68819430-G-C
• chr16-68819430-G-T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PS3_Supporting PM2_Supporting PS4_Moderate

This summary comes from the ClinGen Evidence Repository: The c.1711+5G>A variant in CDH1 is an intronic variant which switches a G to an A in the +5 position of intron 11. This variant is known in five families, three of which meet HDGC criteria (PS4_moderate; PMID:15235021, AmbryGenetics, Invitae, Color and CeTaG internal data). This variant is completely absent from population databases such as gnomAD (PM2_supporting). There is evidence of abnormal RNA expression of this variant allele as a functional consequence of incorrect slicing, but further studies are required to confirm this evidence (PS3_supporting; PMID:15235021). In summary, this variant is classified as a variant of uncertain significance. ACMG/AMP criteria applied, as specified by the ClinGen CDH1 Variant Curation Expert Panel: PS3_supporting, PS4_moderate, PM2_supporting. (CDH1 VCEP specifications version 3.1; 06/26/2023) LINK:https://erepo.genome.network/evrepo/ui/classification/CA645369681/MONDO:0100488/007

• Frequency: Genomes: not found (cov: 31)
• Consequence: CDH1 NM_004360.5 splice_region, intron
• Scores: Splicing: ADA: 0.9989
• Clinical Significance: Uncertain significance reviewed by expert panel P:3 U:3
• Conservation: PhyloP100: 1.36
• 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, 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

ENSG00000260798 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• 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.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDH1	NM_004360.5	MANE Select	c.1711+5G>A		splice_region intron	N/A	NP_004351.1
	CDH1	NM_001317184.2		c.1528+5G>A		splice_region intron	N/A	NP_001304113.1
	CDH1	NM_001317185.2		c.163+5G>A		splice_region intron	N/A	NP_001304114.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDH1	ENST00000261769.10	TSL:1 MANE Select	c.1711+5G>A		splice_region intron	N/A	ENSP00000261769.4
	CDH1	ENST00000422392.6	TSL:1	c.1528+5G>A		splice_region intron	N/A	ENSP00000414946.2
	CDH1	ENST00000562836.5	TSL:1	n.1782+5G>A		splice_region intron	N/A

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: reviewed by expert panel

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.37
CADD	Benign	17
DANN	Benign	0.77
PhyloP100		1.4
Mutation Taster		=6/94	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.83
Splicevardb		3.0
SpliceAI score (max)		0.050		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: rs1131690818; hg19: chr16-68853333;