rs34507583

chr16-68833488-G-Achr16-68833488-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_004360.5(CDH1):c.2638G>A(p.Glu880Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000533 in 1,613,712 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E880G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000055 (0 hom.)
• Consequence: CDH1 NM_004360.5 missense
• Clinical Significance: Benign reviewed by expert panel U:3 B:8
• Conservation: PhyloP100: 8.13

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.05986023).
• BP6: Variant 16-68833488-G-A is Benign according to our data. Variant chr16-68833488-G-A is described in ClinVar as [Benign]. Clinvar id is 184838.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr16-68833488-G-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population eas. gnomad4_exome allele frequency = 0.0000547 (80/1461444) while in subpopulation EAS AF= 0.00169 (67/39700). AF 95% confidence interval is 0.00136. There are 0 homozygotes in gnomad4_exome. There are 45 alleles in male gnomad4_exome subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDH1	NM_004360.5	c.2638G>A	p.Glu880Lys	missense_variant	16/16	ENST00000261769.10
CDH1	NM_001317184.2	c.2455G>A	p.Glu819Lys	missense_variant	15/15
CDH1	NM_001317185.2	c.1090G>A	p.Glu364Lys	missense_variant	16/16
CDH1	NM_001317186.2	c.673G>A	p.Glu225Lys	missense_variant	15/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDH1	ENST00000261769.10	c.2638G>A	p.Glu880Lys	missense_variant	16/16	1	NM_004360.5	P1

Frequencies

GnomAD3 genomes AF: 0.0000394 AC: 6 AN: 152150 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: 0.00115

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

GnomAD3 exomes AF: 0.0000875 AC: 22 AN: 251400 Hom.: 0 AF XY: 0.0000883 AC XY: 12 AN XY: 135880

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000870

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000547 AC: 80 AN: 1461444 Hom.: 0 Cov.: 32 AF XY: 0.0000619 AC XY: 45 AN XY: 727026

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000894

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00169

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.0000829

GnomAD4 genome AF: 0.0000394 AC: 6 AN: 152268 Hom.: 0 Cov.: 32 AF XY: 0.0000403 AC XY: 3 AN XY: 74446

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00116

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000427 Hom.: 0

Bravo AF: 0.0000378

ExAC AF: 0.000123 AC: 15

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Uncertain:3 Benign:8

Revision: reviewed by expert panel

Submissions by phenotype

Hereditary cancer-predisposing syndrome Benign:3

Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jan 13, 2021	- -
Likely benign, criteria provided, single submitter	curation	Sema4, Sema4	Jul 16, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 15, 2021	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. -

Hereditary diffuse gastric adenocarcinoma Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Dec 25, 2023	- -

Malignant tumor of breast Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The CDH1 p.Glu880Lys variant was identified in 2 of 160 proband chromosomes (frequency: 0.0125) from individuals or families with sporadic diffuse gastric cancer (Cho 2017). The variant was identified in dbSNP (rs34507583) as “with uncertain significance allele” and ClinVar (classified as uncertain significance by Color, Ambry Genetics and GeneDx and likely benign by Invitae). The variant was identified in control databases in 22 of 251,400 chromosomes at a frequency of 0.00009 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: East Asian in 16 of 18,394 chromosomes (freq: 0.0009), Latino in 4 of 34,592 chromosomes (freq: 0.0001), South Asian in 1 of 30,616 chromosomes (freq: 0.00003), European in 1 of 113,700 chromosomes (freq: 0.000009), while the variant was not observed in the African, Ashkenazi Jewish, Finnish and Other populations. In one study, in vitro expression of the variant had no observed effect on cell aggregation (Cho 2017) The p.Glu880 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and 1 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -

Hereditary breast ovarian cancer syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

research

Cancer Genomics Group, Japanese Foundation For Cancer Research

May 01, 2019

- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Aug 07, 2023

Variant summary: CDH1 c.2638G>A (p.Glu880Lys) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00036 in 276380 control chromosomes, predominantly at a frequency of 0.00087 within the East Asian subpopulation in the gnomAD database. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 30-fold of the estimated maximal expected allele frequency for a pathogenic variant in CDH1 causing Hereditary Diffuse Gastric Cancer phenotype (2.8e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. c.2638G>A has been reported in the literature in individuals affected with cancer, including diffuse gastric cancer, breast cancer, pancreatic ductal adenocarcinoma and colorectal cancer as well as in unaffected controls (example, Momozawa_2018, Cho_2017, Mandelker_2017, Yurgelun_2017, Ohmoto_2016, Choi_2020, Pan_2022). Additionally, three large-scale case-control studies suggest the carrier frequency of this variant is no different as in the breast cancer cohort, the biliary tract cancer cohort and the Hereditary Colorectal Cancer, respectively (example, Momozawa_2018, Fujita_2020, Okawa_2023). At-least one co-occurrence with another pathogenic variant(s) has been observed at our laboratory (PTEN c.423delT, p.Arg142GlyfsX5), providing supporting evidence for a benign role. At least one publication reports experimental evidence evaluating an impact on protein function. These results showed no damaging effect of this variant through usage of slow aggregation assays demonstrating that cells overexpressing the variant of interest aggregated as efficiently as did wild-type CDH1-overexpressing cells (Cho_2017). The following publications have been ascertained in the context of this evaluation (PMID: 32241597, 26692440, 33309985, 28873162, 30287823, 28522256, 34537906, 28135145, 36243179). Seven submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 with a predominant consensus classification of benign/likely benign (Benign, n=1; likely benign, n=4; VUS, n=2). Based on the evidence outlined above, the variant was classified as benign. -

CDH1-related condition Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 21, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Oct 15, 2019

In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 32426482, 28522256, 30287823, 28135145) -

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

Benign, reviewed by expert panel

curation

ClinGen CDH1 Variant Curation Expert Panel

Sep 25, 2023

The c.2638G>A (p.Glu880Lys) variant results in a missense change in the last exon of CDH1. This variant has been reported in at least five individuals meeting criteria for HDGC (PMID: 28522256, 32426482, 34537906, 32241597). However, this variant is present at a maximum frequency of 0.001153 (6 of 5,204 alleles) in the East Asian subpopulation in gnomAD, which is greater than expected for CDH1-related diffuse gastric and lobular breast cancer (BS1). This variant has also been observed in 112 individuals without DGC, LBC or SRC tumours and whose families do not suggest HDGC (BS2; internal laboratory contributors). In summary, this variant is classified as benign based on ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel: BS1, BS2. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Uncertain	0.010
Cadd	Pathogenic	27
Dann	Pathogenic	1.0
DEOGEN2	Uncertain	0.75	D;T;.
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D;D;D
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.060	T;T;T
MetaSVM	Benign	-0.47	T
MutationAssessor	Uncertain	2.3	M;.;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.68	T
PROVEAN	Uncertain	-2.7	D;.;D
REVEL	Uncertain	0.32
Sift	Uncertain	0.0050	D;.;D
Sift4G	Uncertain	0.022	D;D;D
Polyphen		0.94	P;.;.
Vest4		0.34
MVP		0.88
MPC		0.75
ClinPred		0.66	D
GERP RS		6.2
Varity_R		0.31
gMVP		0.28

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: rs34507583; hg19: chr16-68867391; COSMIC: COSV55738170;