rs1131690823

Positions:

• chr16-68738340-G-A
• chr16-68738340-G-C
• chr16-68738340-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_004360.5(CDH1):​c.92G>A​(p.Gly31Asp) variant causes a missense change. The variant allele was found at a frequency of 0.00000215 in 1,393,600 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • 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: 4.71

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.894

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CDH1	NM_004360.5	c.92G>A	p.Gly31Asp	missense_variant	2/16	ENST00000261769.10	NP_004351.1
CDH1	NM_001317184.2	c.92G>A	p.Gly31Asp	missense_variant	2/15		NP_001304113.1
CDH1	NM_001317185.2	c.-1524G>A		5_prime_UTR_variant	2/16		NP_001304114.1
CDH1	NM_001317186.2	c.-1728G>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.92G>A	p.Gly31Asp	missense_variant	2/16	1	NM_004360.5	ENSP00000261769.4
CDH1	ENST00000422392.6	c.92G>A	p.Gly31Asp	missense_variant	2/15	1		ENSP00000414946.2
CDH1	ENST00000566612.5	n.92G>A		non_coding_transcript_exon_variant	2/15	1		ENSP00000454782.1
CDH1	ENST00000566510.5	n.92G>A		non_coding_transcript_exon_variant	2/15	5		ENSP00000458139.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000215 AC: 3 AN: 1393600 Hom.: 0 Cov.: 31 AF XY: 0.00000437 AC XY: 3 AN XY: 687236

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: 0.00000279

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Nov 21, 2019	This missense variant replaces glycine with aspartic acid at codon 31 of the CDH1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. 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	May 01, 2024	The p.G31D variant (also known as c.92G>A), located in coding exon 2 of the CDH1 gene, results from a G to A substitution at nucleotide position 92. The glycine at codon 31 is replaced by aspartic acid, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Hereditary diffuse gastric adenocarcinoma Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 12, 2023

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 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: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 823156). 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 glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 31 of the CDH1 protein (p.Gly31Asp). -

Familial cancer of breast Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Dec 16, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.71
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.030
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.34	T;T;T;.;.
Eigen	Uncertain	0.40
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Benign	0.85	D;T;D;T;D
M_CAP	Uncertain	0.14	D
MetaRNN	Pathogenic	0.89	D;D;D;D;D
MetaSVM	Uncertain	-0.12	T
MutationAssessor	Pathogenic	2.9	M;.;.;.;M
PrimateAI	Uncertain	0.51	T
PROVEAN	Uncertain	-3.9	D;.;.;.;D
REVEL	Uncertain	0.34
Sift	Uncertain	0.0010	D;.;.;.;D
Sift4G	Uncertain	0.0030	D;D;D;D;D
Polyphen		0.37	B;.;.;.;.
Vest4		0.81
MutPred		0.65		Gain of disorder (P = 0.1075);Gain of disorder (P = 0.1075);Gain of disorder (P = 0.1075);Gain of disorder (P = 0.1075);Gain of disorder (P = 0.1075);
MVP		0.87
MPC		1.0
ClinPred		0.99	D
GERP RS		4.8
Varity_R		0.91
gMVP		0.77

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: rs1131690823; hg19: chr16-68772243;