rs34033771

Variant names:

• chr16-68737345-C-G
• rs34033771
• NM_004360.5:c.-71C>G

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP2 BA1

This summary comes from the ClinGen Evidence Repository: The NM_004360.5(CDH1):c.-71C>G variant has an allele frequency of 0.01628 (1.628%, 251/15418 alleles, 2 homozygotes) in the European (Non-Finnish) subpopulation of the gnomAD v2.1.1 cohort (BA1; BP2). Therefore, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): BA1, BP2. LINK:https://erepo.genome.network/evrepo/ui/classification/CA350015/MONDO:0007648/007

• Frequency:
  • Genomes: 𝑓 0.0092 (8 hom., cov: 33)
  • Exomes 𝑓: 0.012 (99 hom.)
• Consequence: CDH1 NM_004360.5 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Benign reviewed by expert panel U:1 B:14
• Conservation: PhyloP100: -0.210
• Publications: 8 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: Benign. The variant received -9 ACMG points.

• BP2: For more information check the summary or visit ClinGen Evidence Repository.
• BA1: 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.-71C>G		5_prime_UTR_premature_start_codon_gain	Exon 1 of 16	NP_004351.1	A0A0U2ZQU7
	CDH1	NM_004360.5	MANE Select	c.-71C>G		5_prime_UTR	Exon 1 of 16	NP_004351.1	A0A0U2ZQU7
	CDH1	NM_001317184.2		c.-71C>G		5_prime_UTR_premature_start_codon_gain	Exon 1 of 15	NP_001304113.1	P12830-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDH1	ENST00000261769.10	TSL:1 MANE Select	c.-71C>G		5_prime_UTR_premature_start_codon_gain	Exon 1 of 16	ENSP00000261769.4	P12830-1
	CDH1	ENST00000261769.10	TSL:1 MANE Select	c.-71C>G		5_prime_UTR	Exon 1 of 16	ENSP00000261769.4	P12830-1
	CDH1	ENST00000566612.5	TSL:1	n.-71C>G		5_prime_UTR_premature_start_codon_gain	Exon 1 of 15	ENSP00000454782.1	H3BNC6

Frequencies

GnomAD3 genomes AF: 0.00922 AC: 1404 AN: 152212 Hom.: 8 Cov.: 33

Gnomad AFR AF: 0.00174

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00929

Gnomad ASJ AF: 0.00490

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00538

Gnomad FIN AF: 0.0183

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0137

Gnomad OTH AF: 0.00813

GnomAD4 exome AF: 0.0119 AC: 14031 AN: 1176086 Hom.: 99 Cov.: 16 AF XY: 0.0117 AC XY: 6878 AN XY: 588062

African (AFR) AF: 0.00139 AC: 36 AN: 25898

American (AMR) AF: 0.00661 AC: 213 AN: 32226

Ashkenazi Jewish (ASJ) AF: 0.00427 AC: 95 AN: 22274

East Asian (EAS) AF: 0.00 AC: 0 AN: 33878

South Asian (SAS) AF: 0.00582 AC: 415 AN: 71348

European-Finnish (FIN) AF: 0.0204 AC: 681 AN: 33444

Middle Eastern (MID) AF: 0.0113 AC: 41 AN: 3628

European-Non Finnish (NFE) AF: 0.0134 AC: 12054 AN: 902656

Other (OTH) AF: 0.00978 AC: 496 AN: 50734

GnomAD4 genome AF: 0.00922 AC: 1405 AN: 152322 Hom.: 8 Cov.: 33 AF XY: 0.00980 AC XY: 730 AN XY: 74488

African (AFR) AF: 0.00173 AC: 72 AN: 41578

American (AMR) AF: 0.00928 AC: 142 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00490 AC: 17 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00538 AC: 26 AN: 4832

European-Finnish (FIN) AF: 0.0183 AC: 194 AN: 10628

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.0137 AC: 934 AN: 68008

Other (OTH) AF: 0.00852 AC: 18 AN: 2112

Alfa AF: 0.0133 Hom.: 2

Bravo AF: 0.00751

Asia WGS AF: 0.00173 AC: 6 AN: 3474

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	5	Hereditary diffuse gastric adenocarcinoma (5)
-	1	4	not provided (5)
-	-	1	CDH1-related diffuse gastric and lobular breast cancer syndrome (1)
-	-	1	Familial cancer of breast;C0376358:Prostate cancer;C0476089:Endometrial carcinoma;C0919267:Ovarian neoplasm;C1708349:Hereditary diffuse gastric adenocarcinoma;C4551988:Blepharocheilodontic syndrome 1 (1)
-	-	1	Hereditary cancer-predisposing syndrome (1)
-	-	1	not specified (1)
-	-	1	Prostate cancer (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.68
CADD	Benign	11
DANN	Benign	0.79
PhyloP100		-0.21
PromoterAI		0.017	Neutral
Mutation Taster		=300/0	polymorphism

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: rs34033771; hg19: chr16-68771248;