16-68819299-A-G

Variant names:

• chr16-68819299-A-G
• rs776890776
• NM_004360.5:c.1585A>G

Variant summary

Our verdict is Uncertain significance. The variant received -1 ACMG points: 0P and 1B. BS2_Supporting

This summary comes from the ClinGen Evidence Repository: The c.1585A>G (NM_004360.5) variant in CDH1 is a missense variant predicted to predicted to cause substitution of Thr by Ala at amino acid 529 (p.Thr529Ala). This variant has been observed in more than 3 heterozygous individuals without GC, DGC, SRC tumours or LBC and whose families do not suggest HDGC (BS2_Supporting; PMID:30287823, Ambry, Invitae). In summary, this variant is classified as uncertain significance for DGLBCS based on the ACMG/AMP criteria applied, as specified by the ClinGen CDH1 VCEP: BS2_Supporting. (CDH1 VCEP specifications version 3.1; 04/24/2023) LINK:https://erepo.genome.network/evrepo/ui/classification/CA347984/MONDO:0100488/007

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000068 (0 hom.)
• Consequence: CDH1 NM_004360.5 missense
• Clinical Significance: Uncertain significance reviewed by expert panel U:7 B:1
• Conservation: PhyloP100: -0.445
• Publications: 13 publications found

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]

CDH1 Gene-Disease associations (from GenCC):

• blepharocheilodontic syndrome 1

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, Illumina, Labcorp Genetics (formerly Invitae), G2P
• CDH1-related diffuse gastric and lobular breast cancer syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, G2P
• hereditary breast carcinoma

  Inheritance: AD Classification: DEFINITIVE Submitted by: Ambry Genetics
• hereditary diffuse gastric adenocarcinoma

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet
• cleft soft palate

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
• orofacial cleft 3

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
• blepharocheilodontic syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• familial ovarian cancer

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ENSG00000260798 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received -1 ACMG points.

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004360.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDH1	NM_004360.5	MANE Select	c.1585A>G	p.Thr529Ala	missense	Exon 11 of 16	NP_004351.1
	CDH1	NM_001317184.2		c.1402A>G	p.Thr468Ala	missense	Exon 10 of 15	NP_001304113.1
	CDH1	NM_001317185.2		c.37A>G	p.Thr13Ala	missense	Exon 11 of 16	NP_001304114.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CDH1	ENST00000261769.10	TSL:1 MANE Select	c.1585A>G	p.Thr529Ala	missense	Exon 11 of 16	ENSP00000261769.4
	CDH1	ENST00000422392.6	TSL:1	c.1402A>G	p.Thr468Ala	missense	Exon 10 of 15	ENSP00000414946.2
	CDH1	ENST00000562836.5	TSL:1	n.1656A>G		non_coding_transcript_exon	Exon 10 of 15

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.0000239 AC: 6 AN: 251482 AF XY: 0.0000294

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000326

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000684 AC: 10 AN: 1461886 Hom.: 0 Cov.: 32 AF XY: 0.00000825 AC XY: 6 AN XY: 727240

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.000252 AC: 10 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1112012

Other (OTH) AF: 0.00 AC: 0 AN: 60392

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.0000412 AC: 5

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:7 Benign:1

Revision: reviewed by expert panel

Submissions by phenotype

Hereditary diffuse gastric adenocarcinoma Uncertain:3

May 28, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 529 of the CDH1 protein (p.Thr529Ala). This variant is present in population databases (rs776890776, gnomAD 0.04%). This missense change has been observed in individual(s) with diffuse gastric cancer (PMID: 32426482). ClinVar contains an entry for this variant (Variation ID: 220445). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The alanine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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.

Mar 03, 2023

Myriad Genetics, Inc.

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Nov 14, 2017

Counsyl

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com.

Hereditary cancer-predisposing syndrome Uncertain:1 Benign:1

Aug 31, 2017

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Nov 17, 2020

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces threonine with alanine at codon 529 of the CDH1 protein. To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 6/251482 chromosomes 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.

Familial cancer of breast;C0476089:Endometrial carcinoma;C1140680:Ovarian cancer;C1708349:Hereditary diffuse gastric adenocarcinoma;C4551988:Blepharocheilodontic syndrome 1 Uncertain:1

Jun 05, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Malignant tumor of breast Uncertain:1

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The CDH1 p.Thr529Ala variant was not identified in the literature nor was it identified in the COSMIC, MutDB, Insight Colon Cancer Gene Variant Database, or the Zhejiang Colon Cancer Database. The variant was identified in dbSNP (ID: rs776890776) as “With Uncertain significance allele”, and in ClinVar and Clinvitae (1x classified as uncertain significance by Invitae in a case of hereditary diffuse gastric cancer). The variant was identified in control databases in 7 of 246262 chromosomes at a frequency of 0.00003 (Genome Aggregation Database Feb 27, 2017). It was observed in the East Asian population in 7 of 17248 chromosomes (freq: 0.0004); it was not observed in the African, Other, Latino, European Non-Finnish, Ashkenazi Jewish, European Finnish, and South Asian populations. The p.Thr529Ala residue is not conserved in mammals and 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, HumanSpliceFinder) 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.

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

Aug 02, 2023

ClinGen CDH1 Variant Curation Expert Panel

Significance: Uncertain significance

Review Status: reviewed by expert panel

Collection Method: curation

The c.1585A>G (NM_004360.5) variant in CDH1 is a missense variant predicted to predicted to cause substitution of Thr by Ala at amino acid 529 (p.Thr529Ala). This variant has been observed in more than 3 heterozygous individuals without GC, DGC, SRC tumours or LBC and whose families do not suggest HDGC (BS2_Supporting; PMID: 30287823, Ambry, Invitae). In summary, this variant is classified as uncertain significance for DGLBCS based on the ACMG/AMP criteria applied, as specified by the ClinGen CDH1 VCEP: BS2_Supporting. (CDH1 VCEP specifications version 3.1; 04/24/2023)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.056
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	0.0070
DANN	Benign	0.52
DEOGEN2	Benign	0.21	T
Eigen	Benign	-2.1
Eigen_PC	Benign	-2.2
FATHMM_MKL	Benign	0.046	N
LIST_S2	Benign	0.17	T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.024	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	0.050	N
PhyloP100		-0.45
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-0.51	N
REVEL	Benign	0.088
Sift	Benign	0.058	T
Sift4G	Benign	0.085	T
Polyphen		0.0	B
Vest4		0.072
MutPred		0.51		Gain of MoRF binding (P = 0.1152)
MVP		0.54
MPC		0.25
ClinPred		0.038	T
GERP RS		-11
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.026
gMVP		0.20

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

Other links and lift over

dbSNP: rs776890776; hg19: chr16-68853202;