chr16-68813448-G-A

Position:

• chr16-68813448-G-A

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

This summary comes from the ClinGen Evidence Repository: The c.1273G>A (p.Val425Ile) variant results in a conservative missense change in the Cadherin 3 domain of CDH1. This variant was observed in 6 in 152,140 alleles in the gnomAD v3.1.2 population database. This variant was observed in a proband with oral clefting (PMID:27227907). However, this variants has also been observed in more than 10 individuals without GC, DGC, gastric SRC tumours or LBC and whose families do not suggest HDGC (BS2). In summary, this variant meets criteria to be classified as Likely Benign based on the ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel: BS2. (CDH1 VCEP specifications version 3.1; 05/22/2023) LINK:https://erepo.genome.network/evrepo/ui/classification/CA288025/MONDO:0100488/007

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000037 (0 hom.)
• Consequence: CDH1 NM_004360.5 missense
• Clinical Significance: Likely benign reviewed by expert panel U:4 B:7
• Conservation: PhyloP100: 1.49

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 -4 ACMG points.

• BS2: For more information check the summary or visit ClinGen Evidence Repository.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CDH1	NM_004360.5	c.1273G>A	p.Val425Ile	missense_variant	9/16	ENST00000261769.10	NP_004351.1
CDH1	NM_001317185.2	c.-343G>A		5_prime_UTR_variant	9/16		NP_001304114.1
CDH1	NM_001317186.2	c.-547G>A		5_prime_UTR_variant	9/15		NP_001304115.1
CDH1	NM_001317184.2	c.1137+1185G>A		intron_variant			NP_001304113.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDH1	ENST00000261769.10	c.1273G>A	p.Val425Ile	missense_variant	9/16	1	NM_004360.5	ENSP00000261769	P1

Frequencies

GnomAD3 genomes AF: 0.0000394 AC: 6 AN: 152140 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000578

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000398 AC: 10 AN: 251484 Hom.: 0 AF XY: 0.0000294 AC XY: 4 AN XY: 135914

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000527

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000369 AC: 54 AN: 1461884 Hom.: 0 Cov.: 32 AF XY: 0.0000344 AC XY: 25 AN XY: 727246

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.0000580

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000324

Gnomad4 OTH exome AF: 0.0000662

GnomAD4 genome AF: 0.0000394 AC: 6 AN: 152258 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74428

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000579

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000838 Hom.: 0

Bravo AF: 0.0000227

ExAC AF: 0.0000165 AC: 2

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:4 Benign:7

Revision: reviewed by expert panel

Submissions by phenotype

not provided Uncertain:3 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Feb 28, 2023	In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with endometrial or colorectal cancer and in an individual with oral clefting (Jori et al., 2015; Ittiwut et al., 2016; Do et al., 2022); This variant is associated with the following publications: (PMID: 24686850, 27227907, 26517685, 30287823, 32175104, 35098669, 31638429, 15235021, 22850631) -
Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The CDH1 p.Val425Ile variant was not identified in the literature nor was it identified in the MutDB, Insight Colon Cancer Gene Variant Database, Zhejiang Colon Cancer Database, databases. The variant was identified in dbSNP (ID: rs570930882) as With Uncertain significance allele, ClinVar (classified as uncertain significance by GeneDx, Ambry Genetics, Invitae), Cosmic (classified as neutral (score 0.31)), databases. The variant was identified in control databases in 9 of 277228 chromosomes at a frequency of 0.000032 increasing the likelihood that this may be a low frequency benign variant in certain populations of origin (Genome Aggregation Consortium Feb 27, 2017). The p.Val425 residue is conserved in mammals but not in more distantly related organisms however computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; 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, HumanSpliceFinder) do not predict a difference in splicing. The variant is located with the Cadherin-like functional domain, the clinical significance of which cannot be determined. 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	Quest Diagnostics Nichols Institute San Juan Capistrano	Apr 30, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Nov 03, 2021	- -

Hereditary diffuse gastric adenocarcinoma Uncertain:1 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 19, 2023	- -
Uncertain significance, 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_Supporting (PMID: 30311375) -

Hereditary cancer-predisposing syndrome Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Oct 17, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 20, 2020	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. -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

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

Aug 14, 2023

Variant summary: CDH1 c.1273G>A (p.Val425Ile) results in a conservative amino acid change located in the Cadherin-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 5.1e-05 in 273966 control chromosomes (gnomAD and Momozawa_2018). The observed variant frequency is approximately 2.45 fold of the estimated maximal expected allele frequency for a pathogenic variant in CDH1 causing Breast Cancer phenotype (2.1e-05), strongly suggesting that the variant is benign. c.1273G>A has been reported in the literature (e.g. Jori_2015, Kraemer_2019), but these reports do not provide unequivocal conclusions about association of the variant with Breast Cancer. In addition, a large Japanese case-control study found the variant to be not associated with breast cancer risk (Momozawa_2018). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 33309985, 26517685, 31422574, 30287823, 36243179). Eight submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Multiple submitters reported the variant with conflicting assessments ranging from uncertain significance to benign, with the most common (four) being likely benign. Based on the evidence outlined above, the variant was classified as likely benign. -

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 03, 2023

The c.1273G>A (p.Val425Ile) variant results in a conservative missense change in the Cadherin 3 domain of CDH1. This variant was observed in 6 in 152,140 alleles in the gnomAD v3.1.2 population database. This variant was observed in a proband with oral clefting (PMID:27227907). However, this variants has also been observed in more than 10 individuals without GC, DGC, gastric SRC tumours or LBC and whose families do not suggest HDGC (BS2). In summary, this variant meets criteria to be classified as Likely Benign based on the ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel: BS2. (CDH1 VCEP specifications version 3.1; 05/22/2023) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	8.8
DANN	Benign	0.59
DEOGEN2	Benign	0.19	T;T;T;.
Eigen	Benign	-0.87
Eigen_PC	Benign	-0.72
FATHMM_MKL	Benign	0.31	N
LIST_S2	Benign	0.72	T;T;T;T
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.040	T;T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	-0.035	N;.;.;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-0.10	N;.;.;.
REVEL	Benign	0.078
Sift	Benign	1.0	T;.;.;.
Sift4G	Benign	1.0	T;T;T;T
Polyphen		0.021	B;.;.;.
Vest4		0.11
MutPred		0.57		Gain of relative solvent accessibility (P = 0.1571);Gain of relative solvent accessibility (P = 0.1571);Gain of relative solvent accessibility (P = 0.1571);Gain of relative solvent accessibility (P = 0.1571);
MVP		0.66
MPC		0.26
ClinPred		0.044	T
GERP RS		4.1
Varity_R		0.041
gMVP		0.24

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: rs570930882; hg19: chr16-68847351; COSMIC: COSV55731335; COSMIC: COSV55731335;