chr16-68737459-T-A

Variant names:

• chr16-68737459-T-A
• rs370614162
• NM_004360.5:c.44T>A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_004360.5(CDH1):​c.44T>A​(p.Leu15Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000026 in 1,536,874 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000022 (0 hom.)
• Consequence: CDH1 NM_004360.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 2.16

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDH1	NM_004360.5	c.44T>A	p.Leu15Gln	missense_variant	Exon 1 of 16	ENST00000261769.10	NP_004351.1
CDH1	NM_001317184.2	c.44T>A	p.Leu15Gln	missense_variant	Exon 1 of 15		NP_001304113.1
CDH1	NM_001317185.2	c.-1572T>A		5_prime_UTR_variant	Exon 1 of 16		NP_001304114.1
CDH1	NM_001317186.2	c.-1776T>A		5_prime_UTR_variant	Exon 1 of 15		NP_001304115.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDH1	ENST00000261769.10	c.44T>A	p.Leu15Gln	missense_variant	Exon 1 of 16	1	NM_004360.5	ENSP00000261769.4
CDH1	ENST00000422392.6	c.44T>A	p.Leu15Gln	missense_variant	Exon 1 of 15	1		ENSP00000414946.2
CDH1	ENST00000566612.5	n.44T>A		non_coding_transcript_exon_variant	Exon 1 of 15	1		ENSP00000454782.1
CDH1	ENST00000566510.5	n.44T>A		non_coding_transcript_exon_variant	Exon 1 of 15	5		ENSP00000458139.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152196 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000217 AC: 3 AN: 1384678 Hom.: 0 Cov.: 30 AF XY: 0.00000146 AC XY: 1 AN XY: 683942

Gnomad4 AFR exome AF: 0.0000318

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: 0.0000346

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152196 Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1 AN XY: 74360

Gnomad4 AFR AF: 0.0000241

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: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000756

ESP6500AA AF: 0.000323 AC: 1

ESP6500EA AF: 0.00 AC: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:2

Mar 16, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.L15Q variant (also known as c.44T>A), located in coding exon 1 of the CDH1 gene, results from a T to A substitution at nucleotide position 44. The leucine at codon 15 is replaced by glutamine, an amino acid with dissimilar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Jan 22, 2022

Sema4, Sema4

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Hereditary diffuse gastric adenocarcinoma Uncertain:1

Dec 11, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 576714). This variant has not been reported in the literature in individuals affected with CDH1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces leucine, which is neutral and non-polar, with glutamine, which is neutral and polar, at codon 15 of the CDH1 protein (p.Leu15Gln). -

not provided Uncertain:1

Oct 20, 2022

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 15235021) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.022	T
BayesDel_noAF	Benign	-0.27
CADD	Uncertain	25
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.52	D;T;T;.;.
Eigen	Benign	0.17
Eigen_PC	Benign	0.15
FATHMM_MKL	Benign	0.48	N
LIST_S2	Benign	0.72	T;T;T;T;T
M_CAP	Pathogenic	0.53	D
MetaRNN	Uncertain	0.74	D;D;D;D;D
MetaSVM	Benign	-0.80	T
MutationAssessor	Uncertain	2.1	M;.;.;.;M
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-2.1	N;.;.;.;N
REVEL	Uncertain	0.36
Sift	Uncertain	0.013	D;.;.;.;D
Sift4G	Uncertain	0.059	T;D;T;D;T
Polyphen		0.91	P;.;.;.;.
Vest4		0.54
MVP		0.78
MPC		0.33
ClinPred		0.57	D
GERP RS		4.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.49
gMVP		0.51

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: rs370614162; hg19: chr16-68771362;