rs1801023

Variant names:

• chr16-68801851-G-A
• rs1801023
• NM_004360.5:c.345G>A

Your query was ambiguous. Multiple possible variants found:

• chr16-68801851-G-A
• chr16-68801851-G-C
• chr16-68801851-G-T

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 c.345G>A variant has an allele frequency of 0.007677 (0.77%, 235/30,612 alleles, 4 homozygotes) in the South Asian subpopulation of the gnomAD 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/CA293902/MONDO:0007648/007

• Frequency:
  • Genomes: 𝑓 0.0026 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0037 (25 hom.)
• Consequence: CDH1 NM_004360.5 synonymous
• Clinical Significance: Benign reviewed by expert panel B:24
• Conservation: PhyloP100: -5.60
• Publications: 11 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: 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.345G>A	p.Thr115Thr	synonymous	Exon 3 of 16	NP_004351.1	A0A0U2ZQU7
	CDH1	NM_001317184.2		c.345G>A	p.Thr115Thr	synonymous	Exon 3 of 15	NP_001304113.1	P12830-2
	CDH1	NM_001317185.2		c.-1271G>A		5_prime_UTR	Exon 3 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.345G>A	p.Thr115Thr	synonymous	Exon 3 of 16	ENSP00000261769.4	P12830-1
	CDH1	ENST00000422392.6	TSL:1	c.345G>A	p.Thr115Thr	synonymous	Exon 3 of 15	ENSP00000414946.2	P12830-2
	CDH1	ENST00000562836.5	TSL:1	n.416G>A		non_coding_transcript_exon	Exon 2 of 15

Frequencies

GnomAD3 genomes AF: 0.00262 AC: 398 AN: 152168 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.000434

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00216

Gnomad ASJ AF: 0.00836

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00787

Gnomad FIN AF: 0.000377

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00388

Gnomad OTH AF: 0.00478

GnomAD2 exomes AF: 0.00372 AC: 933 AN: 251082 AF XY: 0.00417

Gnomad AFR exome AF: 0.000615

Gnomad AMR exome AF: 0.00208

Gnomad ASJ exome AF: 0.0105

Gnomad EAS exome AF: 0.000217

Gnomad FIN exome AF: 0.000601

Gnomad NFE exome AF: 0.00414

Gnomad OTH exome AF: 0.00376

GnomAD4 exome AF: 0.00373 AC: 5456 AN: 1461852 Hom.: 25 Cov.: 32 AF XY: 0.00383 AC XY: 2786 AN XY: 727222

African (AFR) AF: 0.000538 AC: 18 AN: 33480

American (AMR) AF: 0.00233 AC: 104 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00976 AC: 255 AN: 26136

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39700

South Asian (SAS) AF: 0.00827 AC: 713 AN: 86256

European-Finnish (FIN) AF: 0.000562 AC: 30 AN: 53418

Middle Eastern (MID) AF: 0.0113 AC: 65 AN: 5762

European-Non Finnish (NFE) AF: 0.00362 AC: 4020 AN: 1111984

Other (OTH) AF: 0.00411 AC: 248 AN: 60392

GnomAD4 genome AF: 0.00261 AC: 397 AN: 152286 Hom.: 3 Cov.: 32 AF XY: 0.00282 AC XY: 210 AN XY: 74466

African (AFR) AF: 0.000433 AC: 18 AN: 41556

American (AMR) AF: 0.00216 AC: 33 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00836 AC: 29 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.00767 AC: 37 AN: 4824

European-Finnish (FIN) AF: 0.000377 AC: 4 AN: 10606

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

European-Non Finnish (NFE) AF: 0.00388 AC: 264 AN: 68030

Other (OTH) AF: 0.00473 AC: 10 AN: 2112

Alfa AF: 0.00347 Hom.: 1

Bravo AF: 0.00250

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.00491

EpiControl AF: 0.00533

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	10	not specified (10)
-	-	5	Hereditary diffuse gastric adenocarcinoma (5)
-	-	3	Hereditary cancer-predisposing syndrome (3)
-	-	3	not provided (3)
-	-	1	CDH1-related diffuse gastric and lobular breast cancer syndrome (1)
-	-	1	Malignant tumor of breast (1)
-	-	1	Prostate cancer (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	0.47
DANN	Benign	0.58
PhyloP100		-5.6
Mutation Taster		=99/1	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: rs1801023; hg19: chr16-68835754;