16-68737357-A-AGCCCG

Position:

• chr16-68737357-A-AGCCCG

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.-49_-48insGCCCG variant describes a 5bp insertion in the 5'UTR. The allele is absent from populations in gnomAD, ExAC, 1000 Genomes and ESP (PM2_Supporting; https://gnomad.broadinstitute.org); however, this variant occurs in a low complexity region of the reference genome hg19. To our knowledge, the c.-49_-48insGCCCG variant has not been reported in the literature. Single nucleotide variants at positions c.-51 and c.-49 have been observed at a low frequency in gnomAD, and the c.-49G>T variant has been reported to slightly increase promoter activity as assessed by luciferase reporter assay (PMID:23431106). 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/CV419385/MONDO:0007648/007

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: CDH1 NM_004360.5 5_prime_UTR
• Clinical Significance: Uncertain significance reviewed by expert panel U:2
• Conservation: PhyloP100: -0.296

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.-53_-49dup		5_prime_UTR_variant	1/16	ENST00000261769.10	NP_004351.1
CDH1	NM_001317184.2	c.-53_-49dup		5_prime_UTR_variant	1/15		NP_001304113.1
CDH1	NM_001317185.2	c.-1668_-1664dup		5_prime_UTR_variant	1/16		NP_001304114.1
CDH1	NM_001317186.2	c.-1872_-1868dup		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.-53_-49dup		5_prime_UTR_variant	1/16	1	NM_004360.5	ENSP00000261769	P1
CDH1	ENST00000422392.6	c.-53_-49dup		5_prime_UTR_variant	1/15	1		ENSP00000414946
CDH1	ENST00000566612.5	c.-53_-49dup		5_prime_UTR_variant, NMD_transcript_variant	1/15	1		ENSP00000454782
CDH1	ENST00000566510.5	c.-53_-49dup		5_prime_UTR_variant, NMD_transcript_variant	1/15	5		ENSP00000458139

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000616 AC: 8 AN: 1298252 Hom.: 0 Cov.: 20 AF XY: 0.0000109 AC XY: 7 AN XY: 644086

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000292

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000288

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000595

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: reviewed by expert panel

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jul 02, 2015

This variant is denoted CDH1 c.-53_-49dupGCCCG and describes a duplication of five nucleotides that is 53 base pairs upstream of the CDH1 ATG translational start site in the 5' untranslated region (UTR). The surrounding sequence, with the bases that are duplicated in braces, is CCCG[GCCCG]ACCC. This variant was not observed in approximately 3,300 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations, and this region of the gene is not conserved across evolution. Additionally, this variant does not appear to affect the start codon or the Kozak translational consensus sequence. Although this variant has not, to our knowledge, been published in the literature, there are published variants in this region at c.-49 and c.-54 per HGMD (HGMD) (Stenson 2013). Luciferase reporter assays showed that c.-49G>T contributes to a slight increase in promoter activity, while c.-54G>C significantly decreases (p = 0.003) promoter activity (Nakamura 2002, Chen 2013). Therefore, based on the currently available information, we consider CDH1 c.-53_-49dupGCCCG to be a variant of uncertain significance. -

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 21, 2023

The c.-49_-48insGCCCG variant describes a 5bp insertion in the 5'UTR. The allele is absent from populations in gnomAD, ExAC, 1000 Genomes and ESP (PM2_Supporting; https://gnomad.broadinstitute.org); however, this variant occurs in a low complexity region of the reference genome hg19. To our knowledge, the c.-49_-48insGCCCG variant has not been reported in the literature. Single nucleotide variants at positions c.-51 and c.-49 have been observed at a low frequency in gnomAD, and the c.-49G>T variant has been reported to slightly increase promoter activity as assessed by luciferase reporter assay (PMID: 23431106). 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. -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1064793834; hg19: chr16-68771260;