NM_004360.5(CDH1):c.22C>T (p.Leu8Phe) AND Hereditary diffuse gastric adenocarcinoma

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: May 2, 2021
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV001916423.5

Allele description [Variation Report for NM_004360.5(CDH1):c.22C>T (p.Leu8Phe)]

NM_004360.5(CDH1):c.22C>T (p.Leu8Phe)

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.22C>T (p.Leu8Phe)

HGVS:

NC_000016.10:g.68737437C>T
NG_008021.1:g.5146C>T
NM_001317184.2:c.22C>T
NM_001317185.2:c.-1594C>T
NM_001317186.2:c.-1798C>T
NM_004360.5:c.22C>TMANE SELECT
NP_001304113.1:p.Leu8Phe
NP_004351.1:p.Leu8Phe
LRG_301t1:c.22C>T
LRG_301:g.5146C>T
NC_000016.9:g.68771340C>T
NM_004360.3:c.22C>T

Protein change:

L8F

Links:

dbSNP: rs1234138761

NCBI 1000 Genomes Browser:

rs1234138761

Molecular consequence:

NM_001317185.2:c.-1594C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001317186.2:c.-1798C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001317184.2:c.22C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_004360.5:c.22C>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
SCV002178020	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (May 2, 2021)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 30287823, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002178020

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(May 2, 2021)

germline

clinical testing

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

Help

Summary from all submissions

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

Citations

PubMed

Germline pathogenic variants of 11 breast cancer genes in 7,051 Japanese patients and 11,241 controls.

Momozawa Y, Iwasaki Y, Parsons MT, Kamatani Y, Takahashi A, Tamura C, Katagiri T, Yoshida T, Nakamura S, Sugano K, Miki Y, Hirata M, Matsuda K, Spurdle AB, Kubo M.

Nat Commun. 2018 Oct 4;9(1):4083. doi: 10.1038/s41467-018-06581-8.

PubMed [citation]

PMID:: 30287823
PMCID:: PMC6172276

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):240-242.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From Invitae, SCV002178020.3

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

Description

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. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The phenylalanine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has been observed in individual(s) with breast cancer (PMID: 30287823). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate insufficient coverage at this position in the ExAC database. This sequence change replaces leucine with phenylalanine at codon 8 of the CDH1 protein (p.Leu8Phe). The leucine residue is weakly conserved and there is a small physicochemical difference between leucine and phenylalanine.

#	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

Last Updated: May 1, 2024

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