16-68833422-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 0P and 0B.

The NM_004360.5(CDH1):c.2572G>C(p.Asp858His) variant causes a missense change. The variant allele was found at a frequency of 0.0000267 in 1,461,894 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D858E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000027 (0 hom.)
• Consequence: CDH1 NM_004360.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:5
• Conservation: PhyloP100: 5.75

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 Uncertain_significance. Variant got 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDH1	NM_004360.5	c.2572G>C	p.Asp858His	missense_variant	16/16	ENST00000261769.10
CDH1	NM_001317184.2	c.2389G>C	p.Asp797His	missense_variant	15/15
CDH1	NM_001317185.2	c.1024G>C	p.Asp342His	missense_variant	16/16
CDH1	NM_001317186.2	c.607G>C	p.Asp203His	missense_variant	15/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDH1	ENST00000261769.10	c.2572G>C	p.Asp858His	missense_variant	16/16	1	NM_004360.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000795 AC: 2 AN: 251486 Hom.: 0 AF XY: 0.00 AC XY: 0 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: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000267 AC: 39 AN: 1461894 Hom.: 0 Cov.: 32 AF XY: 0.0000261 AC XY: 19 AN XY: 727248

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: 0.00

Gnomad4 NFE exome AF: 0.0000333

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome Cov.: 32

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	May 22, 2023	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Identified in an individual with pancreatic cancer (Hu et al., 2016); This variant is associated with the following publications: (PMID: 15235021, 22850631, 26296696, 26483394) -
Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The CDH1 p.Asp858His variant was identified in 1 of 192 proband chromosomes (frequency: 0.005) from individuals or families with pancreatic cancer (Hu 2016). The variant was also identified in dbSNP (ID: rs587782025) as "With Uncertain significance allele", ClinVar (classified as uncertain significance by Invitae, Ambry Genetics, GeneDx and Color). The variant was identified in control databases in 2 of 246264 chromosomes at a frequency of 0.000008 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the European in 2 of 111712 chromosomes (freq: 0.00002), but not in the African, Other, Latino, Ashkenazi Jewish, East Asian, Finnish, or South Asian populations. The p.Asp858 residue is conserved across mammals and other organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and 1 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is 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	Nov 12, 2021	This missense variant replaces aspartic acid with histidine at codon 858 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 reported in an individual affected with pancreatic cancer (PMID: 26483394). This variant has been identified in 2/251486 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	Jun 13, 2020	The p.D858H variant (also known as c.2572G>C), located in coding exon 16 of the CDH1 gene, results from a G to C substitution at nucleotide position 2572. The aspartic acid at codon 858 is replaced by histidine, an amino acid with similar properties. This alteration was previously reported in 1/96 individuals with pancreatic ductal adenocarcinoma via multi-gene cancer panel, who were unselected for family history. This individual was noted to have a family history of endometrial cancer, but no family history of breast or pancreatic cancer (Hu C et al. Cancer Epidemiol. Biomarkers Prev., 2016 Jan;25:207-11). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Hereditary diffuse gastric adenocarcinoma Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Dec 30, 2023

This sequence change replaces aspartic acid, which is acidic and polar, with histidine, which is basic and polar, at codon 858 of the CDH1 protein (p.Asp858His). This variant is present in population databases (rs587782025, gnomAD 0.002%). This missense change has been observed in individual(s) with pancreatic cancer (PMID: 26483394). ClinVar contains an entry for this variant (Variation ID: 141803). 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.63
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.30
Cadd	Pathogenic	26
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.62	D;T;.
Eigen	Pathogenic	0.88
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D;D
M_CAP	Uncertain	0.26	D
MetaRNN	Uncertain	0.69	D;D;D
MetaSVM	Uncertain	0.76	D
MutationAssessor	Pathogenic	3.8	H;.;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.74	T
PROVEAN	Pathogenic	-5.7	D;.;D
REVEL	Pathogenic	0.83
Sift	Uncertain	0.0010	D;.;D
Sift4G	Pathogenic	0.0010	D;D;D
Polyphen		1.0	D;.;.
Vest4		0.54
MutPred		0.84		Loss of disorder (P = 0.0568);.;.;
MVP		0.97
MPC		0.98
ClinPred		1.0	D
GERP RS		5.2
Varity_R		0.88
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: rs587782025; hg19: chr16-68867325;