NM_004360.5(CDH1):c.268C>T (p.Arg90Trp) AND Hereditary diffuse gastric adenocarcinoma

Germline classification:: Uncertain significance (3 submissions)
Last evaluated:: Jan 18, 2024
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000410067.11

Allele description [Variation Report for NM_004360.5(CDH1):c.268C>T (p.Arg90Trp)]

NM_004360.5(CDH1):c.268C>T (p.Arg90Trp)

Gene:

CDH1:cadherin 1 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

16q22.1

Genomic location:

Preferred name:

NM_004360.5(CDH1):c.268C>T (p.Arg90Trp)

Other names:

p.R90W:CGG>TGG

HGVS:

NC_000016.10:g.68801774C>T
NG_008021.1:g.69483C>T
NM_001317184.2:c.268C>T
NM_001317185.2:c.-1348C>T
NM_001317186.2:c.-1552C>T
NM_004360.5:c.268C>TMANE SELECT
NP_001304113.1:p.Arg90Trp
NP_004351.1:p.Arg90Trp
LRG_301t1:c.268C>T
LRG_301:g.69483C>T
NC_000016.9:g.68835677C>T
NM_004360.3:c.268C>T
NM_004360.4:c.268C>T
p.R90W

Protein change:

R90W

Links:

dbSNP: rs730881661

NCBI 1000 Genomes Browser:

rs730881661

Molecular consequence:

NM_001317185.2:c.-1348C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001317186.2:c.-1552C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001317184.2:c.268C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_004360.5:c.268C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Hereditary diffuse gastric adenocarcinoma (HDGC)
Synonyms:: Hereditary diffuse gastric cancer
Identifiers:: MONDO: MONDO:0007648; MedGen: C1708349; Orphanet: 26106; OMIM: 137215

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000489601	Counsyl	criteria provided, single submitter (Counsyl Autosomal Dominant Disease Classification criteria (2015))	Uncertain significance (Nov 8, 2016)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID] Counsyl Autosomal Dominant Disease Classification criteria (2015), Citation Link,
SCV000760777	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Jan 18, 2024)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 23555086, 28492532
SCV004020020	Myriad Genetics, Inc.	criteria provided, single submitter (Myriad Autosomal Dominant, Autosomal Recessive and X-Linked Classification Criteria (2023))	Uncertain significance (Mar 6, 2023)	unknown	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000489601

Counsyl

criteria provided, single submitter

(Counsyl Autosomal Dominant Disease Classification criteria (2015))

Uncertain significance
(Nov 8, 2016)

unknown

clinical testing

PubMed (1)
[See all records that cite this PMID]

Counsyl Autosomal Dominant Disease Classification criteria (2015),

Citation Link,

SCV000760777

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Jan 18, 2024)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

SCV004020020

Myriad Genetics, Inc.

criteria provided, single submitter

(Myriad Autosomal Dominant, Autosomal Recessive and X-Linked Classification Criteria (2023))

Uncertain significance
(Mar 6, 2023)

unknown

clinical testing

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Molecular and survival differences between familial and sporadic gastric cancers.

Fang WL, Chang SC, Lan YT, Huang KH, Lo SS, Li AF, Chi CW, Wu CW, Chiou SH.

Biomed Res Int. 2013;2013:396272. doi: 10.1155/2013/396272. Epub 2013 Mar 5.

PubMed [citation]

PMID:: 23555086
PMCID:: PMC3603157

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From Counsyl, SCV000489601.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000760777.8

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 90 of the CDH1 protein (p.Arg90Trp). 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 gastric cancer (PMID: 23555086). ClinVar contains an entry for this variant (Variation ID: 182390). 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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Myriad Genetics, Inc., SCV004020020.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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