NM_004360.5(CDH1):c.377C>A (p.Pro126Gln) AND Hereditary diffuse gastric adenocarcinoma

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Feb 23, 2023
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:: RCV000535540.5

Allele description [Variation Report for NM_004360.5(CDH1):c.377C>A (p.Pro126Gln)]

NM_004360.5(CDH1):c.377C>A (p.Pro126Gln)

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.377C>A (p.Pro126Gln)

HGVS:

NC_000016.10:g.68801883C>A
NG_008021.1:g.69592C>A
NM_001317184.2:c.377C>A
NM_001317185.2:c.-1239C>A
NM_001317186.2:c.-1443C>A
NM_004360.5:c.377C>AMANE SELECT
NP_001304113.1:p.Pro126Gln
NP_004351.1:p.Pro126Gln
LRG_301t1:c.377C>A
LRG_301:g.69592C>A
NC_000016.9:g.68835786C>A
NM_004360.3:c.377C>A
NM_004360.4:c.377C>A

Protein change:

P126Q

Links:

dbSNP: rs746703615

NCBI 1000 Genomes Browser:

rs746703615

Molecular consequence:

NM_001317185.2:c.-1239C>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001317186.2:c.-1443C>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001317184.2:c.377C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_004360.5:c.377C>A - 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
SCV000637822	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Feb 23, 2023)	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

SCV000637822

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Feb 23, 2023)

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. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000637822.4

#	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. RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (Invitae). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The glutamine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. ClinVar contains an entry for this variant (Variation ID: 463778). This missense change has been observed in individual(s) with breast cancer (PMID: 30287823). This variant is present in population databases (rs746703615, gnomAD 0.007%). This sequence change replaces proline, which is neutral and non-polar, with glutamine, which is neutral and polar, at codon 126 of the CDH1 protein (p.Pro126Gln).

#	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: Sep 29, 2024

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