rs34507583

Variant names:

• chr16-68833488-G-A
• rs34507583
• NM_004360.5:c.2638G>A

Your query was ambiguous. Multiple possible variants found:

• chr16-68833488-G-A
• chr16-68833488-G-C

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BS2 BS1

This summary comes from the ClinGen Evidence Repository: The c.2638G>A (p.Glu880Lys) variant results in a missense change in the last exon of CDH1. This variant has been reported in at least five individuals meeting criteria for HDGC (PMID:28522256, 32426482, 34537906, 32241597). However, this variant is present at a maximum frequency of 0.001153 (6 of 5,204 alleles) in the East Asian subpopulation in gnomAD, which is greater than expected for CDH1-related diffuse gastric and lobular breast cancer (BS1). This variant has also been observed in 112 individuals without DGC, LBC or SRC tumours and whose families do not suggest HDGC (BS2; internal laboratory contributors). In summary, this variant is classified as benign based on ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel: BS1, BS2. LINK:https://erepo.genome.network/evrepo/ui/classification/CA190198/MONDO:0100488/007

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000055 (0 hom.)
• Consequence: CDH1 NM_004360.5 missense
• Clinical Significance: Benign reviewed by expert panel U:3 B:8
• Conservation: PhyloP100: 8.13
• Publications: 23 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: Benign. The variant received -8 ACMG points.

• BS1: For more information check the summary or visit ClinGen Evidence Repository.
• BS2: 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDH1	NM_004360.5	MANE Select	c.2638G>A	p.Glu880Lys	missense	Exon 16 of 16	NP_004351.1
	CDH1	NM_001317184.2		c.2455G>A	p.Glu819Lys	missense	Exon 15 of 15	NP_001304113.1
	CDH1	NM_001317185.2		c.1090G>A	p.Glu364Lys	missense	Exon 16 of 16	NP_001304114.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDH1	ENST00000261769.10	TSL:1 MANE Select	c.2638G>A	p.Glu880Lys	missense	Exon 16 of 16	ENSP00000261769.4
	CDH1	ENST00000422392.6	TSL:1	c.2455G>A	p.Glu819Lys	missense	Exon 15 of 15	ENSP00000414946.2
	CDH1	ENST00000562836.5	TSL:1	n.2709G>A		non_coding_transcript_exon	Exon 15 of 15

Frequencies

GnomAD3 genomes AF: 0.0000394 AC: 6 AN: 152150 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00115

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000875 AC: 22 AN: 251400 AF XY: 0.0000883

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000870

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000547 AC: 80 AN: 1461444 Hom.: 0 Cov.: 32 AF XY: 0.0000619 AC XY: 45 AN XY: 727026

African (AFR) AF: 0.00 AC: 0 AN: 33474

American (AMR) AF: 0.0000894 AC: 4 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26136

East Asian (EAS) AF: 0.00169 AC: 67 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86236

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53412

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5522

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111894

Other (OTH) AF: 0.0000829 AC: 5 AN: 60346

GnomAD4 genome AF: 0.0000394 AC: 6 AN: 152268 Hom.: 0 Cov.: 32 AF XY: 0.0000403 AC XY: 3 AN XY: 74446

African (AFR) AF: 0.00 AC: 0 AN: 41550

American (AMR) AF: 0.00 AC: 0 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00116 AC: 6 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10604

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68020

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.0000505 Hom.: 0

Bravo AF: 0.0000378

ExAC AF: 0.000123 AC: 15

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: reviewed by expert panel

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Uncertain	0.010
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.75	D
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.060	T
MetaSVM	Benign	-0.47	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		8.1
PrimateAI	Uncertain	0.68	T
PROVEAN	Uncertain	-2.7	D
REVEL	Uncertain	0.32
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.022	D
Polyphen		0.94	P
Vest4		0.34
MVP		0.88
MPC		0.75
ClinPred		0.66	D
GERP RS		6.2
Varity_R		0.31
gMVP		0.28
Mutation Taster		=42/58	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs34507583; hg19: chr16-68867391;