rs863224729

Positions:

• chr16-68738309-C-A
• chr16-68738309-C-G
• chr16-68738309-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 1P and 1B. PM2_Supporting BS2_Supporting

This summary comes from the ClinGen Evidence Repository: The c.61C>A (p.Leu21Ile) variant results in a non-synonymous amino acid change in exon 2. The A allele has not been observed in the gnomAD population database (PM2_Supporting; http://gnomad.broadinstitute.org). This variant has been observed in at least three individuals without DGC, SRC tumours and whose families do not suggest HDGC (BS2_supporting; SCV000760847.1, SCV000279855.9) In summary, the clinical significance of this variant is uncertain based on ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): PM2_Supporting, BS2_supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA10577531/MONDO:0007648/007

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CDH1 NM_004360.5 missense
• Clinical Significance: Uncertain significance reviewed by expert panel U:3
• Conservation: PhyloP100: 0.584

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 0 ACMG points.

• PM2: For more information check the summary or visit ClinGen Evidence Repository.
• 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.61C>A	p.Leu21Ile	missense_variant	2/16	ENST00000261769.10	NP_004351.1
CDH1	NM_001317184.2	c.61C>A	p.Leu21Ile	missense_variant	2/15		NP_001304113.1
CDH1	NM_001317185.2	c.-1555C>A		5_prime_UTR_variant	2/16		NP_001304114.1
CDH1	NM_001317186.2	c.-1759C>A		5_prime_UTR_variant	2/15		NP_001304115.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDH1	ENST00000261769.10	c.61C>A	p.Leu21Ile	missense_variant	2/16	1	NM_004360.5	ENSP00000261769	P1
CDH1	ENST00000422392.6	c.61C>A	p.Leu21Ile	missense_variant	2/15	1		ENSP00000414946
CDH1	ENST00000566612.5	c.61C>A	p.Leu21Ile	missense_variant, NMD_transcript_variant	2/15	1		ENSP00000454782
CDH1	ENST00000566510.5	c.61C>A	p.Leu21Ile	missense_variant, NMD_transcript_variant	2/15	5		ENSP00000458139

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1398252 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 689734

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 Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: reviewed by expert panel

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Aug 16, 2018

This variant is denoted CDH1 c.61C>A at the cDNA level, p.Leu21Ile (L21I) at the protein level, and results in the change of a Leucine to an Isoleucine (CTC>ATC). This variant has not, to our knowledge, been published in the literature as a pathogenic or benign germline variant. CDH1 Leu21Ile was not observed in large population cohorts (Lek 2016). This variant is located in the protein signal peptide (Brooks-Wilson 2004). In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether CDH1 Leu21Ile is a pathogenic or benign variant. 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

Oct 23, 2023

This sequence change replaces leucine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 21 of the CDH1 protein (p.Leu21Ile). 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: 234812). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. 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.61C>A (p.Leu21Ile) variant results in a non-synonymous amino acid change in exon 2. The A allele has not been observed in the gnomAD population database (PM2_Supporting; http://gnomad.broadinstitute.org). This variant has been observed in at least three individuals without DGC, SRC tumours and whose families do not suggest HDGC (BS2_supporting; SCV000760847.1, SCV000279855.9) In summary, the clinical significance of this variant is uncertain based on ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): PM2_Supporting, BS2_supporting. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	8.9
DANN	Benign	0.77
DEOGEN2	Benign	0.38	T;T;T;.;.
Eigen	Benign	-0.86
Eigen_PC	Benign	-0.85
FATHMM_MKL	Benign	0.22	N
LIST_S2	Benign	0.62	T;T;T;T;T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.21	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.6	L;.;.;.;L
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.54	N;.;.;.;N
REVEL	Benign	0.012
Sift	Benign	0.44	T;.;.;.;T
Sift4G	Benign	0.55	T;T;T;T;T
Polyphen		0.0060	B;.;.;.;.
Vest4		0.51
MutPred		0.37		Gain of sheet (P = 0.0043);Gain of sheet (P = 0.0043);Gain of sheet (P = 0.0043);Gain of sheet (P = 0.0043);Gain of sheet (P = 0.0043);
MVP		0.49
MPC		0.27
ClinPred		0.11	T
GERP RS		2.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.044
gMVP		0.12

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

Publications

LitVar

Other links and lift over

dbSNP: rs863224729; hg19: chr16-68772212;