chr16-68737366-C-G

Variant names:

• chr16-68737366-C-G
• rs876660969
• NM_004360.5:c.-50C>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 1P and 0B. PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The c.-50C>G variant occurs in the 5'UTR. This variant is absent in the gnomAD cohort (PM2_Supporting; https://gnomad.broadinstitute.org); however, this variant occurs in a low complexity region of the reference genome version GRCh37/hg19. To our knowledge, the c.-50C>G variant has not been reported in the literature. Other single nucleotide variants in the CDH1 promoter have been shown to alter promoter activity, the c.-49G>T variant slightly increasing activity and the c.-54G>C variant decreasing activity based on luciferase assays (PMID:23431106, 11996968). In summary, this variant is classified as a variant of uncertain significance based on insufficient ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): PM2_Supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA10577530/MONDO:0007648/007

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000037 (0 hom.)
• Consequence: CDH1 NM_004360.5 5_prime_UTR
• Clinical Significance: Uncertain significance reviewed by expert panel U:3
• Conservation: PhyloP100: 0.170
• Publications: 0 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: Uncertain_significance. The variant received 1 ACMG points.

• PM2: 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.-50C>G		5_prime_UTR	Exon 1 of 16	NP_004351.1	A0A0U2ZQU7
	CDH1	NM_001317184.2		c.-50C>G		5_prime_UTR	Exon 1 of 15	NP_001304113.1	P12830-2
	CDH1	NM_001317185.2		c.-1665C>G		5_prime_UTR	Exon 1 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.-50C>G		5_prime_UTR	Exon 1 of 16	ENSP00000261769.4	P12830-1
	CDH1	ENST00000422392.6	TSL:1	c.-50C>G		5_prime_UTR	Exon 1 of 15	ENSP00000414946.2	P12830-2
	CDH1	ENST00000566612.5	TSL:1	n.-50C>G		non_coding_transcript_exon	Exon 1 of 15	ENSP00000454782.1	H3BNC6

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000371 AC: 5 AN: 1347364 Hom.: 0 Cov.: 26 AF XY: 0.00000450 AC XY: 3 AN XY: 666006

African (AFR) AF: 0.00 AC: 0 AN: 29702

American (AMR) AF: 0.00 AC: 0 AN: 34876

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24362

East Asian (EAS) AF: 0.0000286 AC: 1 AN: 35012

South Asian (SAS) AF: 0.00 AC: 0 AN: 77242

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 34028

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4000

European-Non Finnish (NFE) AF: 0.00000285 AC: 3 AN: 1051664

Other (OTH) AF: 0.0000177 AC: 1 AN: 56478

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	1	-	CDH1-related diffuse gastric and lobular breast cancer syndrome (1)
-	1	-	not provided (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.62
CADD	Benign	13
DANN	Benign	0.85
PhyloP100		0.17
PromoterAI		-0.013	Neutral

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: rs876660969; hg19: chr16-68771269;