rs587780121

chr16-68833365-G-Achr16-68833365-G-Cchr16-68833365-G-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP6 BS2

The NM_004360.5(CDH1):c.2515G>A(p.Gly839Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000192 in 1,614,062 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. G839D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000021 (0 hom.)
• Consequence: CDH1 NM_004360.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7 B:2
• Conservation: PhyloP100: 8.12

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 Likely_benign. Variant got -5 ACMG points.

• BP6: Variant 16-68833365-G-A is Benign according to our data. Variant chr16-68833365-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 127927.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=7, Likely_benign=2}.
• BS2: High AC in GnomAdExome at 13 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDH1	NM_004360.5	c.2515G>A	p.Gly839Ser	missense_variant	16/16	ENST00000261769.10
CDH1	NM_001317184.2	c.2332G>A	p.Gly778Ser	missense_variant	15/15
CDH1	NM_001317185.2	c.967G>A	p.Gly323Ser	missense_variant	16/16
CDH1	NM_001317186.2	c.550G>A	p.Gly184Ser	missense_variant	15/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDH1	ENST00000261769.10	c.2515G>A	p.Gly839Ser	missense_variant	16/16	1	NM_004360.5	P1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152186 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: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000517 AC: 13 AN: 251488 Hom.: 0 AF XY: 0.0000589 AC XY: 8 AN XY: 135916

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000435

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000352

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000205 AC: 30 AN: 1461876 Hom.: 0 Cov.: 32 AF XY: 0.0000206 AC XY: 15 AN XY: 727246

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000202

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000171

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152186 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74338

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000282 Hom.: 0

Bravo AF: 0.0000416

ExAC AF: 0.0000165 AC: 2

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:7 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary diffuse gastric adenocarcinoma Uncertain:4

Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Dec 22, 2015	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Mar 07, 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 18, 2024	This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 839 of the CDH1 protein (p.Gly839Ser). This variant is present in population databases (rs587780121, gnomAD 0.05%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with CDH1-related conditions. ClinVar contains an entry for this variant (Variation ID: 127927). 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. -
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	Not applicable criteria (PMID: 30311375) -

Hereditary cancer-predisposing syndrome Uncertain:2 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Nov 13, 2023	This missense variant replaces glycine with serine at codon 839 of the CDH1 protein. To our knowledge, functional studies have not been reported for this variant. In a large breast cancer case-control study, this variant was reported in 4/60466 cases and 1/53461 unaffected controls, showing inconclusive association with disease (OR=3.537 (95%CI 0.395 to 31.645); p-value=0.38; Leiden Open Variation Database DB-ID CDH1_000192) (PMID: 33471991). This variant has also been reported in an unaffected individual with a family history of gastric and breast cancer (PMID: 36436516). This variant has been identified in 13/251488 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	curation	Sema4, Sema4	Nov 15, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 15, 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. -

not provided Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Sep 23, 2022	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 15235021, 22850631) -
Likely benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jul 08, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.34
BayesDel_addAF	Uncertain	0.036	T
BayesDel_noAF	Pathogenic	0.14
Cadd	Pathogenic	32
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.56	D;T;.
Eigen	Pathogenic	0.90
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D;D;D
M_CAP	Uncertain	0.24	D
MetaRNN	Uncertain	0.65	D;D;D
MetaSVM	Uncertain	0.58	D
MutationAssessor	Pathogenic	3.0	M;.;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.69	T
PROVEAN	Pathogenic	-5.0	D;.;D
REVEL	Pathogenic	0.71
Sift	Pathogenic	0.0	D;.;D
Sift4G	Benign	0.070	T;T;T
Polyphen		1.0	D;.;.
Vest4		0.66
MutPred		0.77		Gain of phosphorylation at G839 (P = 0.0134);.;.;
MVP		0.97
MPC		0.90
ClinPred		0.74	D
GERP RS		6.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.81
gMVP		0.78

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: rs587780121; hg19: chr16-68867268;