rs200932258

Positions:

• chr16-68811697-G-A
• chr16-68811697-G-C
• chr16-68811697-G-T

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM1 BP4_Moderate BS2_Supporting

The NM_004360.5(CDH1):​c.846G>A​(p.Met282Ile) variant causes a missense change. The variant allele was found at a frequency of 0.000039 in 1,613,854 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000059 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000037 (0 hom.)
• Consequence: CDH1 NM_004360.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:9 B:1
• Conservation: PhyloP100: 6.07

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 Likely_benign. Variant got -1 ACMG points.

• PM1: In a domain Cadherin 2 (size 112) in uniprot entity CADH1_HUMAN there are 7 pathogenic changes around while only 3 benign (70%) in NM_004360.5
• BP4: Computational evidence support a benign effect (MetaRNN=0.20799243).
• BS2: High AC in GnomAd4 at 9 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CDH1	NM_004360.5	c.846G>A	p.Met282Ile	missense_variant	7/16	ENST00000261769.10	NP_004351.1
CDH1	NM_001317184.2	c.846G>A	p.Met282Ile	missense_variant	7/15		NP_001304113.1
CDH1	NM_001317185.2	c.-770G>A		5_prime_UTR_variant	7/16		NP_001304114.1
CDH1	NM_001317186.2	c.-974G>A		5_prime_UTR_variant	7/15		NP_001304115.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDH1	ENST00000261769.10	c.846G>A	p.Met282Ile	missense_variant	7/16	1	NM_004360.5	ENSP00000261769.4

Frequencies

GnomAD3 genomes AF: 0.0000592 AC: 9 AN: 152054 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000656

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000471

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000756 AC: 19 AN: 251458 Hom.: 0 AF XY: 0.0000809 AC XY: 11 AN XY: 135900

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: 0.000647

Gnomad NFE exome AF: 0.0000440

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000369 AC: 54 AN: 1461800 Hom.: 0 Cov.: 32 AF XY: 0.0000385 AC XY: 28 AN XY: 727200

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000543

Gnomad4 NFE exome AF: 0.0000144

Gnomad4 OTH exome AF: 0.000116

GnomAD4 genome AF: 0.0000592 AC: 9 AN: 152054 Hom.: 0 Cov.: 32 AF XY: 0.0000808 AC XY: 6 AN XY: 74258

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000656

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000471

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000370 Hom.: 0

Bravo AF: 0.0000340

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ExAC AF: 0.000107 AC: 13

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:9 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2 Benign:1

Uncertain significance, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jun 21, 2023	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 11857408, 17224074, 21575214, 22470475, 26486520, 30363059, 15235021, 22850631, 33471991, 32885271) -
Likely benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Oct 22, 2022	- -

Hereditary diffuse gastric adenocarcinoma Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	St. Jude Molecular Pathology, St. Jude Children's Research Hospital	May 16, 2022	The CDH1 c.846G>A (p.Met282Ile) missense change has a maximum subpopulation frequency of 0.060% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). In silico tools are inconclusive about the effect of this variant on protein function, and to our knowledge functional assays have not been performed. This variant has been reported as a somatic variant in a lobular breast carcinoma (PMID: 33441174) and a ductal breast carcinoma (PMID: 11857408). One individual with this variant is reported in a database of women older than 70 years of age who have never had cancer (FLOSSIES, https://whi.color.com/). To our knowledge, this variant has not been reported in individuals with diffuse gastric and lobular breast cancer syndrome. In summary, this variant meets criteria to be classified as of uncertain significance based on the ACMG/AMP criteria, as specified by the CDH1 Variant Curation Expert Panel (PMID: 30311375): no criteria met. -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 15, 2023	This sequence change replaces methionine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 282 of the CDH1 protein (p.Met282Ile). This variant is present in population databases (rs200932258, gnomAD 0.06%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with breast cancer (PMID: 11857408, 32885271). ClinVar contains an entry for this variant (Variation ID: 219957). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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. -

Hereditary cancer-predisposing syndrome Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Apr 06, 2022	This missense variant replaces methionine with isoleucine at codon 282 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 21/282846 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 28, 2023	The p.M282I variant (also known as c.846G>A), located in coding exon 7 of the CDH1 gene, results from a G to A substitution at nucleotide position 846. The methionine at codon 282 is replaced by isoleucine, an amino acid with highly similar properties. This alteration was identified in an individual diagnosed with breast cancer (Lerner-Ellis J et al. J Cancer Res Clin Oncol, 2021 Mar;147:871-879). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Aug 23, 2022

Variant summary: CDH1 c.846G>A (p.Met282Ile) results in a conservative amino acid change located in the second cadherin repeat domain (IPR002126) 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 8e-05 in 236920 control chromosomes (gnomAD v2.1.1, non-cancer dataset). The observed variant frequency is approximately 4-fold of the estimated maximal expected allele frequency for a pathogenic variant in CDH1 causing Breast Cancer (2.1e-05), suggesting the variant may be benign. c.846G>A has been reported in the literature as a somatic variant in breast cancers (e.g. Lei_2002, Chanock_2007) and as a VUS in a setting of multigene panel testing in at least one individual with a personal and family history of breast cancer (Lerner-Ellis_2021). In a recent large study evaluating breast cancer cases and controls in the Breast Cancer Association Consortium (BCAC), the variant was reported in 10/60466 cases, and was found in 5/53461 controls (Dorling_2021 through LOVD). These reports do 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 submitters have provided clinical-significance assessments for this variant to ClinVar after 2014. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS. -

Malignant tumor of breast Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

- -

Familial cancer of breast Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Mar 11, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.80
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	0.11
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.46	T;T;T;.;.
Eigen	Uncertain	0.20
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.88	D;D;D;D;D
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.21	T;T;T;T;T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	0.59	N;.;.;.;N
PrimateAI	Uncertain	0.60	T
PROVEAN	Uncertain	-3.6	D;.;.;.;D
REVEL	Uncertain	0.38
Sift	Benign	0.033	D;.;.;.;D
Sift4G	Benign	0.20	T;T;T;T;T
Polyphen		1.0	D;.;.;.;.
Vest4		0.54
MutPred		0.49		Loss of disorder (P = 0.0736);Loss of disorder (P = 0.0736);Loss of disorder (P = 0.0736);Loss of disorder (P = 0.0736);Loss of disorder (P = 0.0736);
MVP		0.78
MPC		0.89
ClinPred		0.26	T
GERP RS		5.2
Varity_R		0.69
gMVP		0.73

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: rs200932258; hg19: chr16-68845600; COSMIC: COSV55745771; COSMIC: COSV55745771;