16-68829701-A-T

Variant names:

• chr16-68829701-A-T
• rs587780119
• NM_004360.5:c.2343A>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

This summary comes from the ClinGen Evidence Repository: The c.2343A>T (p.Glu781Asp) missense variant has a frequency of 0.00001 (4 of 282,860) in gnomAD, with a maximum allele frequency of 0.00004 (1 of 24,970) in the African subpopulation (http://gnomad.broadinstitute.org). This variant has been observed in ≥100 individuals without DGC, SRC tumours or LBC and whose families do not suggest HDGC (BS2; SCV000149761.14, SCV000185618.5, SCV000288464.7). Although functional impact of this variant was reported from in vitro assays, functional assays except splicing assay are not applicable to CDH1 according to the CDH1 specific variant interpretation criteria. In summary, the clinical significance of this variant is classified as likely benign based on BS2 alone. ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): BS2. LINK:https://erepo.genome.network/evrepo/ui/classification/CA151521/MONDO:0007648/007

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000044 (0 hom.)
• Consequence: CDH1 NM_004360.5 missense
• Clinical Significance: Likely benign reviewed by expert panel U:6 B:13
• Conservation: PhyloP100: 0.551
• Publications: 10 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

Our verdict: Likely_benign. The variant received -4 ACMG points.

• 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.2343A>T	p.Glu781Asp	missense	Exon 15 of 16	NP_004351.1	A0A0U2ZQU7
	CDH1	NM_001317184.2		c.2160A>T	p.Glu720Asp	missense	Exon 14 of 15	NP_001304113.1	P12830-2
	CDH1	NM_001317185.2		c.795A>T	p.Glu265Asp	missense	Exon 15 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.2343A>T	p.Glu781Asp	missense	Exon 15 of 16	ENSP00000261769.4	P12830-1
	CDH1	ENST00000422392.6	TSL:1	c.2160A>T	p.Glu720Asp	missense	Exon 14 of 15	ENSP00000414946.2	P12830-2
	CDH1	ENST00000562836.5	TSL:1	n.2414A>T		non_coding_transcript_exon	Exon 14 of 15

Frequencies

GnomAD3 genomes AF: 0.0000526 AC: 8 AN: 152164 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000119 AC: 3 AN: 251468 AF XY: 0.0000147

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000438 AC: 64 AN: 1461872 Hom.: 0 Cov.: 32 AF XY: 0.0000385 AC XY: 28 AN XY: 727240

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.0000224 AC: 1 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000540 AC: 60 AN: 1111994

Other (OTH) AF: 0.0000497 AC: 3 AN: 60396

GnomAD4 genome AF: 0.0000526 AC: 8 AN: 152164 Hom.: 0 Cov.: 32 AF XY: 0.0000942 AC XY: 7 AN XY: 74340

African (AFR) AF: 0.0000724 AC: 3 AN: 41440

American (AMR) AF: 0.00 AC: 0 AN: 15280

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68024

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.0000340 Hom.: 0

Bravo AF: 0.0000453

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	2	5	Hereditary diffuse gastric adenocarcinoma (7)
-	1	2	Hereditary cancer-predisposing syndrome (3)
-	2	1	not provided (3)
-	-	2	not specified (2)
-	1	-	Breast and/or ovarian cancer (1)
-	-	1	CDH1-related diffuse gastric and lobular breast cancer syndrome (1)
-	-	1	CDH1-related disorder (1)
-	-	1	Hereditary breast ovarian cancer syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.028	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.21	T
Eigen	Benign	-0.16
Eigen_PC	Benign	0.035
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Benign	0.84	T
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.35	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.23	N
PhyloP100		0.55
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-0.89	N
REVEL	Benign	0.21
Sift	Benign	0.66	T
Sift4G	Benign	0.47	T
Polyphen		0.38	B
Vest4		0.61
MutPred		0.73		Loss of catalytic residue at E781 (P = 0.1453)
MVP		0.77
MPC		0.45
ClinPred		0.41	T
GERP RS		5.9
Varity_R		0.15
gMVP		0.61
Mutation Taster		=21/79	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: rs587780119; hg19: chr16-68863604;