16-68822138-G-A

Variant names:

• chr16-68822138-G-A
• rs33935154
• NM_004360.5:c.1849G>A

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BA1

This summary comes from the ClinGen Evidence Repository: The c.1849G>A (p.Ala617Thr) variant has an allele frequency of 0.04479 (4.5%, 1,076/24,022 alleles) in the African subpopulation of the gnomAD cohort (BA1). In summary, 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. LINK:https://erepo.genome.network/evrepo/ui/classification/CA121991/MONDO:0007648/007

• Frequency:
  • Genomes: 𝑓 0.013 (49 hom., cov: 31)
  • Exomes 𝑓: 0.0014 (36 hom.)
• Consequence: CDH1 NM_004360.5 missense
• Clinical Significance: Benign reviewed by expert panel P:2 B:28 O:1
• Conservation: PhyloP100: 1.25
• Publications: 58 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: Benign. The variant received -8 ACMG points.

• 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.1849G>A	p.Ala617Thr	missense	Exon 12 of 16	NP_004351.1	A0A0U2ZQU7
	CDH1	NM_001317184.2		c.1666G>A	p.Ala556Thr	missense	Exon 11 of 15	NP_001304113.1	P12830-2
	CDH1	NM_001317185.2		c.301G>A	p.Ala101Thr	missense	Exon 12 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.1849G>A	p.Ala617Thr	missense	Exon 12 of 16	ENSP00000261769.4	P12830-1
	CDH1	ENST00000422392.6	TSL:1	c.1666G>A	p.Ala556Thr	missense	Exon 11 of 15	ENSP00000414946.2	P12830-2
	CDH1	ENST00000562836.5	TSL:1	n.1920G>A		non_coding_transcript_exon	Exon 11 of 15

Frequencies

GnomAD3 genomes AF: 0.0129 AC: 1969 AN: 152098 Hom.: 49 Cov.: 31

Gnomad AFR AF: 0.0448

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00537

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000279

Gnomad OTH AF: 0.00526

GnomAD2 exomes AF: 0.00349 AC: 878 AN: 251466 AF XY: 0.00252

Gnomad AFR exome AF: 0.0458

Gnomad AMR exome AF: 0.00295

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.000185

Gnomad OTH exome AF: 0.00147

GnomAD4 exome AF: 0.00143 AC: 2097 AN: 1461870 Hom.: 36 Cov.: 32 AF XY: 0.00127 AC XY: 924 AN XY: 727242

African (AFR) AF: 0.0475 AC: 1589 AN: 33476

American (AMR) AF: 0.00315 AC: 141 AN: 44724

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86258

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53418

Middle Eastern (MID) AF: 0.00243 AC: 14 AN: 5768

European-Non Finnish (NFE) AF: 0.000174 AC: 193 AN: 1111996

Other (OTH) AF: 0.00258 AC: 156 AN: 60394

GnomAD4 genome AF: 0.0130 AC: 1974 AN: 152216 Hom.: 49 Cov.: 31 AF XY: 0.0125 AC XY: 929 AN XY: 74412

African (AFR) AF: 0.0448 AC: 1861 AN: 41522

American (AMR) AF: 0.00537 AC: 82 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000279 AC: 19 AN: 68018

Other (OTH) AF: 0.00521 AC: 11 AN: 2112

Alfa AF: 0.00433 Hom.: 45

Bravo AF: 0.0144

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.0471 AC: 207

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00422 AC: 513

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.000327

EpiControl AF: 0.000296

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	8	not specified (9)
1	-	6	Hereditary diffuse gastric adenocarcinoma (7)
-	-	6	Hereditary cancer-predisposing syndrome (6)
-	-	4	not provided (4)
-	-	1	Breast and/or ovarian cancer (1)
-	-	1	CDH1-related diffuse gastric and lobular breast cancer syndrome (1)
1	-	-	Endometrial carcinoma (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	Malignant tumor of breast (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.089
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	19
DANN	Benign	0.97
DEOGEN2	Benign	0.26	T
Eigen	Benign	-0.62
Eigen_PC	Benign	-0.60
FATHMM_MKL	Benign	0.015	N
LIST_S2	Benign	0.80	T
MetaRNN	Benign	0.0056	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	1.5	L
PhyloP100		1.3
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.72	N
REVEL	Benign	0.087
Sift	Benign	0.51	T
Sift4G	Benign	0.52	T
Polyphen		0.040	B
Vest4		0.067
MVP		0.74
MPC		0.26
ClinPred		0.0033	T
GERP RS		3.5
Varity_R		0.037
gMVP		0.39
Mutation Taster		=96/4	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs33935154; hg19: chr16-68856041; COSMIC: COSV55727851; COSMIC: COSV55727851;