16-68815553-C-T

Variant names:

• chr16-68815553-C-T
• rs114861467
• NM_004360.5:c.1359C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001317185.2(CDH1):​c.-190C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000793 in 1,614,230 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). The gene CDH1 is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.000092 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000078 (1 hom.)
• Consequence: CDH1 NM_001317185.2 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:15
• Conservation: PhyloP100: -1.74
• Publications: 3 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

Specifications for CDH1 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BP6: Variant 16-68815553-C-T is Benign according to our data. Variant chr16-68815553-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 184324.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. GnomAdExome4 allele frequency = 0.000078 (114/1461880) while in subpopulation AMR AF = 0.00116 (52/44724). AF 95% confidence interval is 0.00091. There are 1 homozygotes in GnomAdExome4. There are 59 alleles in the male GnomAdExome4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 14 Unknown,AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001317185.2. 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.1359C>T	p.His453His	synonymous	Exon 10 of 16	NP_004351.1	A0A0U2ZQU7
	CDH1	NM_001317185.2		c.-190C>T		5_prime_UTR_premature_start_codon_gain	Exon 10 of 16	NP_001304114.1
	CDH1	NM_001317186.2		c.-461C>T		5_prime_UTR_premature_start_codon_gain	Exon 10 of 15	NP_001304115.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDH1	ENST00000261769.10	TSL:1 MANE Select	c.1359C>T	p.His453His	synonymous	Exon 10 of 16	ENSP00000261769.4	P12830-1
	CDH1	ENST00000422392.6	TSL:1	c.1176C>T	p.His392His	synonymous	Exon 9 of 15	ENSP00000414946.2	P12830-2
	CDH1	ENST00000562836.5	TSL:1	n.1430C>T		non_coding_transcript_exon	Exon 9 of 15

Frequencies

GnomAD3 genomes AF: 0.0000920 AC: 14 AN: 152232 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00135

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000247 AC: 62 AN: 251478 AF XY: 0.000258

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00124

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.000326

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.0000780 AC: 114 AN: 1461880 Hom.: 1 Cov.: 32 AF XY: 0.0000811 AC XY: 59 AN XY: 727238

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

American (AMR) AF: 0.00116 AC: 52 AN: 44724

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

East Asian (EAS) AF: 0.000428 AC: 17 AN: 39700

South Asian (SAS) AF: 0.000313 AC: 27 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.0000108 AC: 12 AN: 1112002

Other (OTH) AF: 0.0000993 AC: 6 AN: 60396

GnomAD4 genome AF: 0.0000919 AC: 14 AN: 152350 Hom.: 0 Cov.: 32 AF XY: 0.0000805 AC XY: 6 AN XY: 74508

African (AFR) AF: 0.00 AC: 0 AN: 41584

American (AMR) AF: 0.000392 AC: 6 AN: 15304

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

East Asian (EAS) AF: 0.00135 AC: 7 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68040

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.0000868 Hom.: 0

Bravo AF: 0.000140

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	Hereditary diffuse gastric adenocarcinoma (4)
-	-	4	not specified (4)
-	-	3	Hereditary cancer-predisposing syndrome (3)
-	-	3	not provided (3)
-	-	1	Hereditary breast ovarian cancer syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	0.94
DANN	Benign	0.82
PhyloP100		-1.7
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: rs114861467; hg19: chr16-68849456; COSMIC: COSV55735708; COSMIC: COSV55735708;