rs199886166

chr16-68813472-G-Achr16-68813472-G-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 2P and 14B. PM1 BP4_Moderate BP6_Very_Strong BS2

The NM_004360.5(CDH1):c.1297G>A(p.Asp433Asn) variant causes a missense change. The variant allele was found at a frequency of 0.0000502 in 1,614,044 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D433G) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.000079 (1 hom., cov: 32)
  • Exomes 𝑓: 0.000047 (0 hom.)
• Consequence: CDH1 NM_004360.5 missense
• Clinical Significance: Likely benign reviewed by expert panel U:7 B:11
• Conservation: PhyloP100: 3.89

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 Benign. Variant got -12 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 16 uncertain in NM_004360.5
• BP4: Computational evidence support a benign effect (MetaRNN=0.11900696).
• BP6: Variant 16-68813472-G-A is Benign according to our data. Variant chr16-68813472-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 127910.Status of the report is reviewed_by_expert_panel, 3 stars.
• BS2: High AC in GnomAd at 12 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDH1	NM_004360.5	c.1297G>A	p.Asp433Asn	missense_variant	9/16	ENST00000261769.10
CDH1	NM_001317185.2	c.-319G>A		5_prime_UTR_variant	9/16
CDH1	NM_001317186.2	c.-523G>A		5_prime_UTR_variant	9/15
CDH1	NM_001317184.2	c.1137+1209G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDH1	ENST00000261769.10	c.1297G>A	p.Asp433Asn	missense_variant	9/16	1	NM_004360.5	P1

Frequencies

GnomAD3 genomes AF: 0.0000789 AC: 12 AN: 152174 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.0000517 AC: 13 AN: 251484 Hom.: 0 AF XY: 0.0000589 AC XY: 8 AN XY: 135912

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000893

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000472 AC: 69 AN: 1461870 Hom.: 0 Cov.: 32 AF XY: 0.0000454 AC XY: 33 AN XY: 727242

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00134

Gnomad4 EAS exome AF: 0.000126

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000180

Gnomad4 OTH exome AF: 0.000116

GnomAD4 genome AF: 0.0000789 AC: 12 AN: 152174 Hom.: 1 Cov.: 32 AF XY: 0.0000538 AC XY: 4 AN XY: 74336

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000655

Gnomad4 ASJ AF: 0.00202

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.000478

Alfa AF: 0.0000494 Hom.: 0

Bravo AF: 0.0000680

ExAC AF: 0.0000247 AC: 3

EpiCase AF: 0.0000545

EpiControl AF: 0.000119

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:7 Benign:11

Revision: reviewed by expert panel

Submissions by phenotype

Hereditary diffuse gastric adenocarcinoma Uncertain:4 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Mar 07, 2023	This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk. -
Uncertain significance, no assertion criteria provided	clinical testing	Knight Diagnostic Laboratories, Oregon Health and Sciences University	Sep 26, 2015	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Pittsburgh Clinical Genomics Laboratory, University of Pittsburgh Medical Center	Jun 21, 2018	This sequence variant is a single nucleotide substitution (G>A) that results in an aspartic acid to asparagine amino acid change at residue 433 in the CDH1 protein. The variant is rare, and is present in 3/120502 alleles (0.002%) in the ExAC database. The variant has been observed in a sporadic gastric cancer patient (PMID: 23435907) and at least two women with breast cancer, including one case of lobular breast cancer (PMID: 20921021) and one breast cancer of unspecified type (PMID: 26976419). This variant lies in cadherin repeat domain 3, but the aspartic acid at this position is not well conserved in this domain; several mammalian species have asparagine at this position. Additionally, the variant lies near a splice site, but mRNA analysis indicates no effects on proper splicing (PMID: 23435907). The majority of in silico tools queried predict that substituting asparagine for aspartic acid at this protein position will have a neutral effect on protein function. However, no functional tests to confirm these predictions have been performed, to our knowledge. At this time, we consider this to be a variant of uncertain significance. -
Likely benign, criteria provided, single submitter	clinical testing	European Reference Network on Genetic Tumour Risk Syndromes (ERN-GENTURIS), i3s - Instituto de Investigação e Inovação em Saúde, University of Porto	Aug 01, 2022	BS2 (PMID: 30311375) -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Feb 17, 2016	- -

not provided Uncertain:3 Benign:2

Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The CDH1 p.Asp433Asn variant was identified in 4 of 2232 proband chromosomes (frequency: 0.002) from individuals or families with lobular breast carcinoma, metanephric adenoma or gastric cancer and was not identified in 850 control chromosomes from healthy individuals (Ding 2018, Li 2013, Schrader 2011, Tung 2016). The variant was also identified in dbSNP (ID: rs199886166) as "With Uncertain significance allele" and ClinVar (classified as uncertain significance by Invitae, GeneDx, Ambry Genetics and four other submitters). The variant was identified in control databases in 12 of 246262 chromosomes at a frequency of 0.00005 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European in 2 of 111710 chromosomes (freq: 0.00002), Ashkenazi Jewish in 8 of 9850 chromosomes (freq: 0.0008), and East Asian in 2 of 17248 chromosomes (freq: 0.0001), while the variant was not observed in the African, Other, Latino, Finnish, and South Asian populations. RNA analysis of the p.Asp433Asn variant demonstrated normal-length mRNA, suggesting this variant does not induce splicing defects in E-cadherin (Li 2013). The p.Asp433 residue is not conserved in mammals and 5 of 5 computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. 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. -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2022	CDH1: BP4 -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 10, 2020	The CDH1 c.1297G>A; p.Asp433Asn variant (rs199886166) has been described in the literature in individuals with breast cancer without causality of the variant established (Momozawa 2018, Schrader 2011). The variant has been classified as likely benign by an expert panel in the ClinVar database but is also classified as a variant of uncertain significance by several sources (Variation ID: 127910). The variant is found in the general population with an overall allele frequency of 0.005% (13/251,484 alleles) in the Genome Aggregation Database. The aspartic acid at codon 433 is moderately conserved computational analyses predict that this variant is neutral (REVEL: 0.09). Due to limited information, the clinical significance of the p.Asp433Asn variant is uncertain at this time. References: Momozawa et al. Germline pathogenic variants of 11 breast cancer genes in 7,051 Japanese patients and 11,241 controls. Nat Commun. 2018 Oct 4;9(1):4083. Schrader et al. Germline mutations in CDH1 are infrequent in women with early-onset or familial lobular breast cancers. J Med Genet. 2011 Jan;48(1):64-8. -
Likely benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Aug 10, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Nov 20, 2019	In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Observed in individuals with breast or gastric cancer (Schrader 2011, Li 2013, Tung 2016, Momozawa 2018); This variant is associated with the following publications: (PMID: 22722839, 30287823, 20921021, 23435907, 26976419, 26759166, 25096233, 26486520, 26182300) -

Hereditary cancer-predisposing syndrome Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Oct 12, 2018	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. -
Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jun 08, 2015	- -
Benign, criteria provided, single submitter	curation	Sema4, Sema4	Jul 21, 2020	- -

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 18, 2023	Variant summary: CDH1 c.1297G>A (p.Asp433Asn) results in a conservative amino acid change located in the Cadherrin-like domain (IPR002126) of the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 5.2e-05 in 252334 control chromosomes. The observed variant frequency is approximately 2 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 benign. The variant has been reported in the literature in breast and gastric cancer patients, without strong evidence for causality (Schrader_2010, Tung_2016, Li_2013). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Diffuse Gastric Cancer. One functional study reported the variant to have no impact on splicing, yielding normal-sized mRNA (Li_2013), however additional functional studies have not been reported. The following publications have been ascertained in the context of this evaluation (PMID: 22722839, 20921021, 26976419, 23435907, 30287823, 28061482). 15 submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified as benign/likely benign (n=8) and VUS (n=7). Based on the evidence outlined above, the variant was classified as likely benign. -

CDH1-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 26, 2024

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). -

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.1297G>A (p.Asp433Asn) variant has been observed in >10 individuals without a diagnosis of diffuse gastric cancer, signet ring tumor or lobular breast cancer and whose family histories do not suggest HDGC (BS2; internal laboratory contributors). In summary, the clinical significance of this variant is classified as likely benign based on BS2 alone. ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): BS2. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.65
Cadd	Benign	19
Dann	Uncertain	0.99
DEOGEN2	Benign	0.31	T;T;T;.
Eigen	Benign	-0.43
Eigen_PC	Benign	-0.34
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.71	T;T;T;T
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.12	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.93	L;.;.;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-1.6	N;.;.;.
REVEL	Benign	0.090
Sift	Benign	0.089	T;.;.;.
Sift4G	Benign	0.061	T;T;T;T
Polyphen		0.14	B;.;.;.
Vest4		0.24
MVP		0.76
MPC		0.27
ClinPred		0.11	T
GERP RS		2.8
Varity_R		0.093
gMVP		0.46

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: rs199886166; hg19: chr16-68847375; COSMIC: COSV55730580; COSMIC: COSV55730580;