rs556110297

chr16-68813346-G-Achr16-68813346-G-Cchr16-68813346-G-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_004360.5(CDH1):c.1171G>A(p.Val391Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000039 in 1,614,146 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V391F) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000042 (1 hom.)
• Consequence: CDH1 NM_004360.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:12 B:2
• Conservation: PhyloP100: 0.977

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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.042580932).
• BP6: Variant 16-68813346-G-A is Benign according to our data. Variant chr16-68813346-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 184651.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=12, Likely_benign=2}.
• BS2: High AC in GnomAdExome at 12 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDH1	NM_004360.5	c.1171G>A	p.Val391Ile	missense_variant	9/16	ENST00000261769.10
CDH1	NM_001317185.2	c.-445G>A		5_prime_UTR_variant	9/16
CDH1	NM_001317186.2	c.-649G>A		5_prime_UTR_variant	9/15
CDH1	NM_001317184.2	c.1137+1083G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDH1	ENST00000261769.10	c.1171G>A	p.Val391Ile	missense_variant	9/16	1	NM_004360.5	P1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152146 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000477 AC: 12 AN: 251472 Hom.: 0 AF XY: 0.0000294 AC XY: 4 AN XY: 135908

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: 0.0000980

Gnomad FIN exome AF: 0.0000924

Gnomad NFE exome AF: 0.0000615

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000417 AC: 61 AN: 1461882 Hom.: 1 Cov.: 32 AF XY: 0.0000330 AC XY: 24 AN XY: 727242

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000128

Gnomad4 FIN exome AF: 0.0000562

Gnomad4 NFE exome AF: 0.0000378

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152264 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74436

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000658 Hom.: 0

Bravo AF: 0.0000113

ExAC AF: 0.0000906 AC: 11

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:12 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary diffuse gastric adenocarcinoma Uncertain:5

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) -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Oct 27, 2016	- -
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	Invitae	Jan 28, 2024	This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 391 of the CDH1 protein (p.Val391Ile). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with breast cancer (PMID: 25186627, 36436516). ClinVar contains an entry for this variant (Variation ID: 184651). 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 tolerated. 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 10, 2023	The CDH1 gene sequence change replaces valine with isoleucine at codon 391 of the CDH1 protein (p.Val391Ile). The valine residue is weakly conserved and there is a small physicochemical difference between valine and isoleucine. This variant is present in population databases (rs556110297, ExAC 0.02%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been observed in an individual affected with breast cancer (PMID: 25186627). ClinVar contains an entry for this variant (Variation ID: 184651). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align- GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. Therefore, it has been classified as a Variant of Uncertain Significance. Heterozygous pathogenic and likely pathogenic variants in the CDH1 gene cause increased susceptibility to breast cancer (OMIM# 114480). -

not provided Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Apr 11, 2018	The CDH1 c.1171G>A; p.Val391Ile variant (rs556110297), to our knowledge, is not reported in the medical literature. This variant is reported as uncertain by multiple laboratories in ClinVar (Variation ID: 184651), and found in the general population with an allele frequency of 0.005% (13/246240 alleles) in the Genome Aggregation Database. The valine at codon 391 is weakly conserved and computational algorithms (SIFT, PolyPhen2) predict this variant is tolerated. However, given the limited information regarding this variant, its clinical significance is uncertain at this time. -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Nov 21, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jul 28, 2023	In silico analysis supports that this missense variant does not alter protein structure/function; Identified in individuals with a personal history of breast or other cancers, but also present in unaffected controls (Tung et al., 2015; Dorling et al., 2021; Yin et al., 2022); This variant is associated with the following publications: (PMID: 25186627, 30287823, 33471991, 15235021, 22850631, 29641532, 36436516, 35171259) -

Hereditary cancer-predisposing syndrome Uncertain:1 Benign:2

Uncertain significance, criteria provided, single submitter	curation	Sema4, Sema4	Feb 12, 2022	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Aug 16, 2021	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. -
Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jun 27, 2023	- -

Familial cancer of breast Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	The CDH1 gene sequence change replaces valine with isoleucine at codon 391 of the CDH1 protein (p.Val391Ile). The valine residue is weakly conserved and there is a small physicochemical difference between valine and isoleucine. This variant is present in population databases (rs556110297, ExAC 0.02%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been observed in an individual affected with breast cancer (PMID: 25186627). ClinVar contains an entry for this variant (Variation ID: 184651). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align- GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Dec 02, 2019	- -

Familial cancer of breast;C0376358:Malignant tumor of prostate;C0476089:Endometrial carcinoma;C0919267:Neoplasm of ovary;C1708349:Hereditary diffuse gastric adenocarcinoma;C4551988:Blepharocheilodontic syndrome 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.60
Cadd	Benign	5.6
Dann	Benign	0.87
DEOGEN2	Benign	0.22	T;T;T;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.27	N
LIST_S2	Benign	0.70	T;T;T;T
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.043	T;T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	2.0	M;.;.;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.54	N;.;.;.
REVEL	Benign	0.085
Sift	Benign	0.20	T;.;.;.
Sift4G	Benign	0.32	T;T;T;T
Polyphen		0.0010	B;.;.;.
Vest4		0.17
MutPred		0.45		Gain of catalytic residue at L396 (P = 0.0316);Gain of catalytic residue at L396 (P = 0.0316);Gain of catalytic residue at L396 (P = 0.0316);Gain of catalytic residue at L396 (P = 0.0316);
MVP		0.42
MPC		0.20
ClinPred		0.026	T
GERP RS		3.0
Varity_R		0.051
gMVP		0.25

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: rs556110297; hg19: chr16-68847249; COSMIC: COSV99028475; COSMIC: COSV99028475;