16-68737344-T-C

Position:

• chr16-68737344-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 1P and 0B. PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The c.-72T>C variant occurs in the 5'UTR at a nucleotide that is not highly conserved. This variant is absent from population databases (PM2_supporting). To our knowledge, this variant has not been observed in an individual with DGC, LBC, SRC tumours or whose family history suggests HDGC. In summary, this variant meets criteria to be classified as a variant of uncertain significance based on ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel: PM2_supporting. (CDH1 VCEP specifications version 3.1; 03/27/2023) LINK:https://erepo.genome.network/evrepo/ui/classification/CA2229914895/MONDO:0100488/007

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000026 (0 hom.)
• Consequence: CDH1 NM_004360.5 5_prime_UTR
• Clinical Significance: Uncertain significance reviewed by expert panel U:1
• Conservation: PhyloP100: -0.698

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CDH1	NM_004360.5	c.-72T>C		5_prime_UTR_variant	1/16	ENST00000261769.10	NP_004351.1
CDH1	NM_001317184.2	c.-72T>C		5_prime_UTR_variant	1/15		NP_001304113.1
CDH1	NM_001317185.2	c.-1687T>C		5_prime_UTR_variant	1/16		NP_001304114.1
CDH1	NM_001317186.2	c.-1891T>C		5_prime_UTR_variant	1/15		NP_001304115.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDH1	ENST00000261769.10	c.-72T>C		5_prime_UTR_variant	1/16	1	NM_004360.5	ENSP00000261769	P1
CDH1	ENST00000566612.5	c.-72T>C		5_prime_UTR_variant, NMD_transcript_variant	1/15	1		ENSP00000454782
CDH1	ENST00000422392.6			upstream_gene_variant		1		ENSP00000414946
CDH1	ENST00000566510.5			upstream_gene_variant		5		ENSP00000458139

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000256 AC: 3 AN: 1170096 Hom.: 0 Cov.: 16 AF XY: 0.00000342 AC XY: 2 AN XY: 585448

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000887

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: reviewed by expert panel

Submissions by phenotype

CDH1-related diffuse gastric and lobular breast cancer syndrome Uncertain:1

Uncertain significance, reviewed by expert panel

curation

ClinGen CDH1 Variant Curation Expert Panel

Aug 03, 2023

The c.-72T>C variant occurs in the 5'UTR at a nucleotide that is not highly conserved. This variant is absent from population databases (PM2_supporting). To our knowledge, this variant has not been observed in an individual with DGC, LBC, SRC tumours or whose family history suggests HDGC. In summary, this variant meets criteria to be classified as a variant of uncertain significance based on ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel: PM2_supporting. (CDH1 VCEP specifications version 3.1; 03/27/2023) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.71
CADD	Benign	12
DANN	Benign	0.73

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1962418098; hg19: chr16-68771247;