chr16-68810317-T-G

Position:

• chr16-68810317-T-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BS2 BA1

This summary comes from the ClinGen Evidence Repository: The c.808T>G (p.Ser270Ala) variant has a maximum subpopulation frequency of 0.002269 (0.2269%, 57 of 25124 alleles) in the European (Finnish) subpopulation of the gnomAD v2.1.1 cohort (BA1). This variant has also has been observed in more than 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; SCV000185687.6, SCV000254832.8). In summary, this variant meets criteria to be classified as benign based the ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): BA1, BS2. LINK:https://erepo.genome.network/evrepo/ui/classification/CA294235/MONDO:0007648/007

• Frequency:
  • Genomes: 𝑓 0.00035 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00017 (0 hom.)
• Consequence: CDH1 NM_004360.5 missense
• Clinical Significance: Benign reviewed by expert panel U:2 B:12 O:1
• Conservation: PhyloP100: 2.27

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.

• BS2: For more information check the summary or visit ClinGen Evidence Repository.
• BA1: 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.808T>G	p.Ser270Ala	missense_variant	6/16	ENST00000261769.10	NP_004351.1
CDH1	NM_001317184.2	c.808T>G	p.Ser270Ala	missense_variant	6/15		NP_001304113.1
CDH1	NM_001317185.2	c.-808T>G		5_prime_UTR_variant	6/16		NP_001304114.1
CDH1	NM_001317186.2	c.-1012T>G		5_prime_UTR_variant	6/15		NP_001304115.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDH1	ENST00000261769.10	c.808T>G	p.Ser270Ala	missense_variant	6/16	1	NM_004360.5	ENSP00000261769	P1

Frequencies

GnomAD3 genomes AF: 0.000349 AC: 53 AN: 152022 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000242

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: 0.00245

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000368

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.000338 AC: 85 AN: 251452 Hom.: 0 AF XY: 0.000316 AC XY: 43 AN XY: 135892

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00217

Gnomad NFE exome AF: 0.000273

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.000174 AC: 255 AN: 1461810 Hom.: 0 Cov.: 31 AF XY: 0.000165 AC XY: 120 AN XY: 727210

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: 0.00241

Gnomad4 NFE exome AF: 0.000103

Gnomad4 OTH exome AF: 0.000182

GnomAD4 genome AF: 0.000349 AC: 53 AN: 152022 Hom.: 0 Cov.: 31 AF XY: 0.000417 AC XY: 31 AN XY: 74264

Gnomad4 AFR AF: 0.0000242

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00245

Gnomad4 NFE AF: 0.000368

Gnomad4 OTH AF: 0.000479

Alfa AF: 0.000300 Hom.: 0

Bravo AF: 0.0000340

ExAC AF: 0.000371 AC: 45

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Benign

Submissions summary: Uncertain:2 Benign:12 Other:1

Revision: reviewed by expert panel

Submissions by phenotype

Hereditary diffuse gastric adenocarcinoma Uncertain:1 Benign:5 Other:1

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 25, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Counsyl	May 23, 2018	- -
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) -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
not provided, no classification provided	literature only	Laboratório de Genética Humana e Médica, Universidade Federal do Pará	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Mar 06, 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. -

Hereditary cancer-predisposing syndrome Uncertain:1 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 17, 2016	- -
Uncertain significance, criteria provided, single submitter	curation	Sema4, Sema4	Mar 01, 2022	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Aug 22, 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. -

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 01, 2019	Variant summary: CDH1 c.808T>G (p.Ser270Ala) results in a conservative amino acid change located in the second cadherin repeat (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 0.00044 in 282828 control chromosomes, predominantly at a frequency of 0.0023 within the Finnish subpopulation in the gnomAD database. The observed variant frequency within Finnish control individuals in the gnomAD database is approximately 80 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 Finnish origin. c.808T>G has been reported in the literature in individuals affected with gastric cancer and breast/ovary cancer (e.g. Ikonen 2001, Brovkina 2018). These reports however, do not provide unequivocal conclusions about association of the variant with Hereditary Diffuse Gastric Cancer. At least one publication reported experimental evidence evaluating an impact on protein function, demonstarating that the variant resulted in a strong adhesion but a bit lower than that of WT, the effect on cell migration in a wound closure assay was similar to WT, however, the variant protein was not activatable in CHO cells (Petrova 2016). The significance of these results at the cellular level remains however unclear. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (4 classifying it as likely benign, and 1 as a VUS). Based on the evidence outlined above, the variant was classified as likely benign. -
Likely benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 13, 2019	In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 26182300, 11948460, 19725995, 17545690, 11705864, 22098830, 27582386, 29928469, 30333958, 32426482) -
Likely benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Sep 19, 2020	- -

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

Benign, reviewed by expert panel

curation

ClinGen CDH1 Variant Curation Expert Panel

Aug 17, 2023

The c.808T>G (p.Ser270Ala) variant has a maximum subpopulation frequency of 0.002269 (0.2269%, 57 of 25124 alleles) in the European (Finnish) subpopulation of the gnomAD v2.1.1 cohort (BA1). This variant has also has been observed in more than 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; SCV000185687.6, SCV000254832.8). In summary, this variant meets criteria to be classified as benign based the ACMG/AMP criteria applied, as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): BA1, BS2. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.19
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.31	T;T;T;.;.
Eigen	Benign	-0.21
Eigen_PC	Benign	-0.22
FATHMM_MKL	Benign	0.25	N
LIST_S2	Benign	0.70	T;T;T;T;T
M_CAP	Benign	0.030	D
MetaRNN	Benign	0.025	T;T;T;T;T
MetaSVM	Benign	-0.77	T
MutationAssessor	Benign	1.3	L;.;.;.;L
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-2.1	N;.;.;.;N
REVEL	Uncertain	0.29
Sift	Benign	0.082	T;.;.;.;T
Sift4G	Benign	0.094	T;T;T;T;T
Polyphen		0.25	B;.;.;.;.
Vest4		0.33
MVP		0.80
MPC		0.52
ClinPred		0.064	T
GERP RS		5.2
Varity_R		0.18
gMVP		0.21

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs587776399; hg19: chr16-68844220;