rs1064794231

Positions:

• chr16-68810240-A-G
• chr16-68810240-A-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. BS2 PM2_Supporting

This summary comes from the ClinGen Evidence Repository: The c.731A>G (p.Asp244Gly) variant results in a non-conservative amino acid substitution in the Cadherin-1 domain. This variant has a frequency of 6.57x10-6 (1 in 152,170 alleles) in gnomAD (PM2_supporting) and has been reported in one family meeting IGCLC criteria for HDGC (PMID:10319582). However, this variant has been observed in more than 30 families without DGC, LBC or SRC tumours and whose families do not suggest HDGC (BS2; unpublished). Functional studies of the p.Asp244Gly variant suggest that this variant may affect the subcellular localization of E-cadherin and regulation of cell adhesion (PMID:27582386, 28301459). In summary, this variant is classified as likely benign based on ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel: BS2, PM2_supporting. LINK:https://erepo.genome.network/evrepo/ui/classification/CA16620242/MONDO:0100488/007

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000010 (0 hom.)
• Consequence: CDH1 NM_004360.5 missense
• Clinical Significance: Likely benign reviewed by expert panel P:1 U:3 B:3
• Conservation: PhyloP100: 4.89

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 Likely_benign. Variant got -3 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDH1	NM_004360.5	c.731A>G	p.Asp244Gly	missense_variant	6/16	ENST00000261769.10
CDH1	NM_001317184.2	c.731A>G	p.Asp244Gly	missense_variant	6/15
CDH1	NM_001317185.2	c.-885A>G		5_prime_UTR_variant	6/16
CDH1	NM_001317186.2	c.-1089A>G		5_prime_UTR_variant	6/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDH1	ENST00000261769.10	c.731A>G	p.Asp244Gly	missense_variant	6/16	1	NM_004360.5	P1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152170 Hom.: 0 Cov.: 31

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 AF: 0.0000103 AC: 15 AN: 1461864 Hom.: 0 Cov.: 32 AF XY: 0.00000963 AC XY: 7 AN XY: 727236

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: 0.00000809

Gnomad4 OTH exome AF: 0.0000993

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152170 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 74350

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: Likely benign

Submissions summary: Pathogenic:1 Uncertain:3 Benign:3

Revision: reviewed by expert panel

Submissions by phenotype

not provided Pathogenic:1 Uncertain:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Sep 20, 2019	The frequency of this variant in the general population, 0.0000066 (1/152170 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in an individual with gastric cancer (PMIDs: 10319582 (1999)). Functional studies state that the variant results in loss of cytoplasmic membrane localization (PMID: 28301459 (2017)), as well as inhibits basic E-cadherin adhesion function (PMID: 27582386 (2016)), and is considered destabilizing (PMID: 22470475 (2012)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Sep 25, 2018	This variant is denoted CDH1 c.731A>G at the cDNA level, p.Asp244Gly (D244G) at the protein level, and results in the change of an Aspartic Acid to a Glycine (GAT>GGT). This variant was observed in at least one individual with a personal and family history of gastric cancer (Yoon 1999). Functional studies suggest that this variant may result in decreased adhesion, increased migration, and loss of E-cadherin cytoplasmic membrane localization compared to wild type (Petrova 2016, Ghoumid 2017). CDH1 Asp244Gly was not observed in large population cohorts (Lek 2016). This variant is located in the Cadherin 1 domain (Brooks-Wilson 2004, Figueiredo 2013, UniProt). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether CDH1 Asp244Gly is a pathogenic or benign variant. We consider it to be a variant of uncertain significance. -

Hereditary cancer-predisposing syndrome Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Sep 08, 2020	This missense variant replaces aspartic acid with glycine at codon 244 of the CDH1 protein. Computational prediction tool suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold ≤0.5, PMID: 27666373). Functional studies reported this variant to be partially functional in cell adhesion, migration and subcellular localization (PMID: 27582386, 28301459). This variant has been reported in an individual affected with gastric cancer with positive family history of the disease (PMID: 10319582). 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. -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jun 15, 2023	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Familial cancer of breast Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Sep 05, 2023

- -

Hereditary diffuse gastric adenocarcinoma Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 03, 2024

- -

CDH1-related diffuse gastric and lobular breast cancer syndrome Benign:1

Likely benign, reviewed by expert panel

curation

ClinGen CDH1 Variant Curation Expert Panel

Aug 17, 2023

The c.731A>G (p.Asp244Gly) variant results in a non-conservative amino acid substitution in the Cadherin-1 domain. This variant has a frequency of 6.57x10-6 (1 in 152,170 alleles) in gnomAD (PM2_supporting) and has been reported in one family meeting IGCLC criteria for HDGC (PMID: 10319582). However, this variant has been observed in more than 30 families without DGC, LBC or SRC tumours and whose families do not suggest HDGC (BS2; unpublished). Functional studies of the p.Asp244Gly variant suggest that this variant may affect the subcellular localization of E-cadherin and regulation of cell adhesion (PMID: 27582386, 28301459). In summary, this variant is classified as likely benign based on ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel: BS2, PM2_supporting. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.32
BayesDel_addAF	Uncertain	0.074	D
BayesDel_noAF	Benign	-0.13
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.46	T;T;T;.;.
Eigen	Benign	0.12
Eigen_PC	Benign	0.13
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.84	T;D;T;D;T
M_CAP	Benign	0.031	D
MetaRNN	Pathogenic	0.75	D;D;D;D;D
MetaSVM	Benign	-0.86	T
MutationAssessor	Benign	1.2	L;.;.;.;L
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.36	T
PROVEAN	Uncertain	-4.0	D;.;.;.;D
REVEL	Uncertain	0.31
Sift	Uncertain	0.019	D;.;.;.;D
Sift4G	Benign	0.21	T;D;T;T;T
Polyphen		0.97	D;.;.;.;.
Vest4		0.48
MutPred		0.81		Gain of catalytic residue at E243 (P = 0.0674);Gain of catalytic residue at E243 (P = 0.0674);Gain of catalytic residue at E243 (P = 0.0674);Gain of catalytic residue at E243 (P = 0.0674);Gain of catalytic residue at E243 (P = 0.0674);
MVP		0.88
MPC		1.0
ClinPred		0.93	D
GERP RS		5.2
Varity_R		0.40
gMVP		0.56

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: rs1064794231; hg19: chr16-68844143;