chr16-68738362-G-C

Position:

• chr16-68738362-G-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Very_Strong BP7 BS2_Supporting

The NM_004360.5(CDH1):​c.114G>C​(p.Thr38Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000387 in 1,551,036 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000036 (0 hom.)
• Consequence: CDH1 NM_004360.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.0580

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.65).
• BP6: Variant 16-68738362-G-C is Benign according to our data. Variant chr16-68738362-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 184482.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.058 with no splicing effect.
• BS2: High AC in GnomAdExome4 at 5 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.114G>C	p.Thr38Thr	synonymous_variant	2/16	ENST00000261769.10	NP_004351.1
CDH1	NM_001317184.2	c.114G>C	p.Thr38Thr	synonymous_variant	2/15		NP_001304113.1
CDH1	NM_001317185.2	c.-1502G>C		5_prime_UTR_variant	2/16		NP_001304114.1
CDH1	NM_001317186.2	c.-1706G>C		5_prime_UTR_variant	2/15		NP_001304115.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDH1	ENST00000261769.10	c.114G>C	p.Thr38Thr	synonymous_variant	2/16	1	NM_004360.5	ENSP00000261769.4
CDH1	ENST00000422392.6	c.114G>C	p.Thr38Thr	synonymous_variant	2/15	1		ENSP00000414946.2
CDH1	ENST00000566612.5	n.114G>C		non_coding_transcript_exon_variant	2/15	1		ENSP00000454782.1
CDH1	ENST00000566510.5	n.114G>C		non_coding_transcript_exon_variant	2/15	5		ENSP00000458139.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152200 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: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000357 AC: 5 AN: 1398836 Hom.: 0 Cov.: 31 AF XY: 0.00000290 AC XY: 2 AN XY: 689922

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000280

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000690

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152200 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74360

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.00000378

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary diffuse gastric adenocarcinoma Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 16, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Sep 11, 2024	This variant is considered benign. This variant is a silent/synonymous amino acid change and it is not expected to impact splicing. -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 13, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Apr 15, 2019	- -

Hereditary cancer-predisposing syndrome Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Feb 16, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Mar 29, 2017	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. -

Malignant tumor of breast Benign:1

Likely benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The CDH1 p.Thr38= variant was not identified in the literature, nor was it identified in COSMIC, Zhejiang Colon Cancer Databases. The variant was identified in dbSNP (ID: rs786201492) as With Likely benign allele, Clinvar database (classified as likely benign by Ambry Genetics, Invitae), Clinvitae databases. The variant was identified in control databases in 1 of 30924 chromosomes at a frequency of 0.00003 (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include East Asian in 1 of 1620 chromosomes (freq: 0.0006), while the variant was not observed in the African, Other, Latino, European, Ashkenazi Jewish, Finnish, and South Asian populations. The p.Thr38= variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. In addition, in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.65
CADD	Benign	6.2
DANN	Benign	0.72

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: rs786201492; hg19: chr16-68772265;