rs587781311

Positions:

• chr16-68829694-G-A
• chr16-68829694-G-C
• chr16-68829694-G-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP2_Strong BS2

This summary comes from the ClinGen Evidence Repository: The c.2336G>A (NM_004360.5) variant in CDH1 is a missense variant predicted to cause substitution of arginine by glutamine at amino acid 779 (p.Arg779Gln). This variant was observed in the homozygous state in an individual without a personal and/or family history of diffuse gastric cancer, lobular breast cancer (BP2_Strong; internal clinical data). This variant has been observed in more than 10 (134) individuals without a diagnosis of diffuse gastric cancer, signet ring tumor or lobular breast cancer and whose family histories do not suggest HDGC. (BS2; PMID:29522266, 36436516; ClinVar SCVs: SCV000172951.7, SCV000288462.10, SCV000210875.16; internal lab contributors). In summary, this variant meets the criteria to be classified as benign for hereditary diffuse gastric cancer based on the ACMG/AMP criteria applied, as specified by the ClinGen CDH1 variant curation expert panel (Variant Interpretation Guidelines Version 3.1): BS2, BP2_S. LINK:https://erepo.genome.network/evrepo/ui/classification/CA293940/MONDO:0007648/007

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000027 (1 hom.)
• Consequence: CDH1 NM_004360.5 missense
• Clinical Significance: Benign reviewed by expert panel U:8 B:3
• Conservation: PhyloP100: 8.01

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BP2: For more information check the summary or visit ClinGen Evidence Repository.
• 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.2336G>A	p.Arg779Gln	missense_variant	15/16	ENST00000261769.10	NP_004351.1
CDH1	NM_001317184.2	c.2153G>A	p.Arg718Gln	missense_variant	14/15		NP_001304113.1
CDH1	NM_001317185.2	c.788G>A	p.Arg263Gln	missense_variant	15/16		NP_001304114.1
CDH1	NM_001317186.2	c.371G>A	p.Arg124Gln	missense_variant	14/15		NP_001304115.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDH1	ENST00000261769.10	c.2336G>A	p.Arg779Gln	missense_variant	15/16	1	NM_004360.5	ENSP00000261769.4

Frequencies

GnomAD3 genomes AF: 0.0000526 AC: 8 AN: 152064 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.0000159 AC: 4 AN: 251462 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135906

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: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000267 AC: 39 AN: 1461876 Hom.: 1 Cov.: 32 AF XY: 0.0000344 AC XY: 25 AN XY: 727238

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000315

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome AF: 0.0000526 AC: 8 AN: 152064 Hom.: 0 Cov.: 32 AF XY: 0.0000808 AC XY: 6 AN XY: 74278

Gnomad4 AFR AF: 0.0000483

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.000478

Alfa AF: 0.0000564 Hom.: 0

Bravo AF: 0.0000567

ExAC AF: 0.0000247 AC: 3

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Benign

Submissions summary: Uncertain:8 Benign:3

Revision: reviewed by expert panel

Submissions by phenotype

Hereditary diffuse gastric adenocarcinoma Uncertain:3 Benign:2

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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	May 12, 2016	- -
Benign, reviewed by expert panel	curation	ClinGen CDH1 Variant Curation Expert Panel	Mar 25, 2024	The c.2336G>A (NM_004360.5) variant in CDH1 is a missense variant predicted to cause substitution of arginine by glutamine at amino acid 779 (p.Arg779Gln). This variant was observed in the homozygous state in an individual without a personal and/or family history of diffuse gastric cancer, lobular breast cancer (BP2_Strong; internal clinical data). This variant has been observed in more than 10 (134) individuals without a diagnosis of diffuse gastric cancer, signet ring tumor or lobular breast cancer and whose family histories do not suggest HDGC. (BS2; PMID: 29522266, 36436516; ClinVar SCVs: SCV000172951.7, SCV000288462.10, SCV000210875.16; internal lab contributors). In summary, this variant meets the criteria to be classified as benign for hereditary diffuse gastric cancer based on the ACMG/AMP criteria applied, as specified by the ClinGen CDH1 variant curation expert panel (Variant Interpretation Guidelines Version 3.1): BS2, BP2_S. -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 20, 2024	- -
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 Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Apr 17, 2023	This missense variant replaces arginine with glutamine at codon 779 of the CDH1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been performed for this variant. This variant has been reported in individuals with breast cancer (PMID: 29522266, Lovejoy et al. 2018). In a large breast cancer case-control study conducted by the BRIDGES consortium, this variant was reported in 6/60466 cases and 1/53461 unaffected controls, showing inconclusive association with disease (OR=5.305 (95%CI 0.639 to 44.07); p-value=0.13; Leiden Open Variation Database DB-ID CDH1_000359) (PMID: 33471991). This variant has been identified in 5/282808 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. -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Aug 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 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Feb 03, 2023

Variant summary: CDH1 c.2336G>A (p.Arg779Gln) results in a conservative amino acid change located in the cadherin, cytoplasmic domain (IPR000233) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 251462 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2336G>A has been reported in the literature in one individual affected with breast cancer (Hauke_2018). This report does not provide unequivocal conclusions about association of the variant with breast cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified it as either VUS (n=4) or likely benign (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance. -

CDH1-related disorder Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 23, 2024

The CDH1 c.2336G>A variant is predicted to result in the amino acid substitution p.Arg779Gln. This variant has been reported in multiple individuals with a personal or familial history of breast cancer (Table S2, Hauke et al. 2018. PubMed ID: 29522266; Table S5, Garcia-Pelaez et al. 2022. PubMed ID: 36436516). This variant has interpretations ranging from benign to uncertain in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/140840/). This variant is reported in 0.0040% of alleles in individuals of African descent in gnomAD. Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jun 05, 2023

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with personal and/or family history of breast cancer (Hauke et al., 2018; Garcia-Pelaez et al., 2023); This variant is associated with the following publications: (PMID: 27499925, 28522829, 26643872, 22850631, 15235021, 36436516, 29522266) -

Familial cancer of breast Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Oct 30, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Uncertain	0.063	T
BayesDel_noAF	Uncertain	-0.080
CADD	Pathogenic	31
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.34	T;T;.
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.84
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.98	D;D;D
M_CAP	Benign	0.030	D
MetaRNN	Uncertain	0.46	T;T;T
MetaSVM	Benign	-0.50	T
MutationAssessor	Uncertain	2.8	M;.;.
PrimateAI	Uncertain	0.65	T
PROVEAN	Uncertain	-2.5	N;.;N
REVEL	Uncertain	0.37
Sift	Benign	0.030	D;.;D
Sift4G	Benign	0.21	T;T;T
Polyphen		1.0	D;.;.
Vest4		0.61
MutPred		0.60		Loss of stability (P = 0.1532);.;.;
MVP		0.88
MPC		0.98
ClinPred		0.96	D
GERP RS		5.9
Varity_R		0.33
gMVP		0.66

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: rs587781311; hg19: chr16-68863597; COSMIC: COSV99932332;