16-68738294-C-A

Position:

• chr16-68738294-C-A

Variant summary

Our verdict is Uncertain significance. Variant got -1 ACMG points: 0P and 1B. BS2_Supporting

This summary comes from the ClinGen Evidence Repository: The c.49-3C>A variant has been observed in at least three individuals without DGC, SRC tumours or LBC and whose families do not suggest HDGC (BS2_supporting; SCV000822625.1, SCV000570129.4, SCV000665064.2). In summary, the clinical significance of this variant is uncertain based on ACMP/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): BS2_supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA16620228/MONDO:0007648/007

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CDH1 NM_004360.5 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.9581
• Clinical Significance: Uncertain significance reviewed by expert panel U:6
• Conservation: PhyloP100: 0.972

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.

• BS2: 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.49-3C>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000261769.10	NP_004351.1
CDH1	NM_001317184.2	c.49-3C>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant			NP_001304113.1
CDH1	NM_001317185.2	c.-1567-3C>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant			NP_001304114.1
CDH1	NM_001317186.2	c.-1771-3C>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant			NP_001304115.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDH1	ENST00000261769.10	c.49-3C>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_004360.5	ENSP00000261769	P1
CDH1	ENST00000422392.6	c.49-3C>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1		ENSP00000414946
CDH1	ENST00000566612.5	c.49-3C>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant, NMD_transcript_variant		1		ENSP00000454782
CDH1	ENST00000566510.5	c.49-3C>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant, NMD_transcript_variant		5		ENSP00000458139

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152180 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

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

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1389576 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 686140

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

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 AF: 0.00000657 AC: 1 AN: 152180 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74336

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:6

Revision: reviewed by expert panel

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	May 10, 2022	This variant causes a C to A nucleotide substitution at the -3 position of intron 1 of the CDH1 gene. Splice site prediction tools suggest that this variant may have a significant impact on RNA splicing. However, this prediction has not been confirmed in published RNA studies. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Jan 10, 2024	The c.49-3C>A intronic variant results from a C to A substitution 3 nucleotides upstream from coding exon 2 in the CDH1 gene. This nucleotide position is well conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will result in the creation or strengthening of a novel splice acceptor site; however, direct evidence is insufficient at this time (Ambry internal data). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Apr 27, 2016

This variant is denoted CDH1 c.49-3C>A or IVS1-3C>A and consists of a C>A nucleotide substitution at the -3 position of intron 1 of the CDH1 gene. Multiple in silico models predict this variant may disrupt the nearby natural splice acceptor site and to possibly cause abnormal gene splicing; however, in the absence of RNA or functional studies, the actual effect of this variant is unknown. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. CDH1 c.49-3C>A was not observed in approximately 4,900 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. The cytosine (C) nucleotide that is altered is conserved among mammals. Based on currently available information, it is unclear whether CDH1 c.49-3C>A is pathogenic or benign. We consider it to be a variant of uncertain significance. -

Hereditary diffuse gastric adenocarcinoma Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 18, 2023

This sequence change falls in intron 1 of the CDH1 gene. It does not directly change the encoded amino acid sequence of the CDH1 protein. It affects a nucleotide within the consensus splice site. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with CDH1-related conditions. ClinVar contains an entry for this variant (Variation ID: 421050). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as 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.49-3C>A variant has been observed in at least three individuals without DGC, SRC tumours or LBC and whose families do not suggest HDGC (BS2_supporting; SCV000822625.1, SCV000570129.4, SCV000665064.2). In summary, the clinical significance of this variant is uncertain based on ACMP/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): BS2_supporting. -

Familial cancer of breast Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Jul 19, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.35
CADD	Benign	21
DANN	Benign	0.88

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.96
dbscSNV1_RF	Benign	0.66
SpliceAI score (max)		0.55		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.55		Position offset: 24

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

Publications

LitVar

Other links and lift over

dbSNP: rs587782366; hg19: chr16-68772197;