NM_004360.5(CDH1):c.1004G>A (p.Arg335Gln) AND Hereditary cancer-predisposing syndrome

Clinical significance:Conflicting interpretations of pathogenicity, Likely benign(1);Uncertain significance(1) (Last evaluated: Sep 11, 2020)

Review status:1 star out of maximum of 4 stars

criteria provided, conflicting interpretations

Based on:
2 submissions [Details]
Record status:
current
Accession:
RCV000115832.10

Allele description [Variation Report for NM_004360.5(CDH1):c.1004G>A (p.Arg335Gln)]

NM_004360.5(CDH1):c.1004G>A (p.Arg335Gln)

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.1004G>A (p.Arg335Gln)
Other names:
p.R335Q:CGA>CAA
HGVS:
  • NC_000016.10:g.68811855G>A
  • NG_008021.1:g.79564G>A
  • NM_001317184.2:c.1004G>A
  • NM_001317185.2:c.-612G>A
  • NM_001317186.2:c.-816G>A
  • NM_004360.5:c.1004G>AMANE SELECT
  • NP_001304113.1:p.Arg335Gln
  • NP_004351.1:p.Arg335Gln
  • LRG_301t1:c.1004G>A
  • LRG_301:g.79564G>A
  • NC_000016.9:g.68845758G>A
  • NM_004360.3:c.1004G>A
  • NM_004360.4:c.1004G>A
  • p.R335Q
Protein change:
R335Q
Links:
dbSNP: rs373364873
NCBI 1000 Genomes Browser:
rs373364873
Molecular consequence:
  • NM_001317185.2:c.-612G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001317186.2:c.-816G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001317184.2:c.1004G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_004360.5:c.1004G>A - missense variant - [Sequence Ontology: SO:0001583]
Observations:
1

Condition(s)

Name:
Hereditary cancer-predisposing syndrome
Synonyms:
Neoplastic Syndromes, Hereditary; Tumor predisposition; Cancer predisposition; See all synonyms [MedGen]
Identifiers:
MONDO: MONDO:0015356; MedGen: C0027672

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000185512Ambry Geneticscriteria provided, single submitter
Likely benign
(Sep 11, 2020)
germlineclinical testing

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

Citation Link,

SCV000684319Color Health, Inccriteria provided, single submitter
Uncertain significance
(Dec 4, 2019)
germlineclinical testing

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

Description

This missense variant replaces arginine with glutamine at codon 335 of the CDH1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has been reported in an individual affected with gastric cancer (PMID: 12414534, 12532420) and an individual affected with colorectal cancer (PMID: 29212164). This variant has been identified in 7/282636 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.

SCV000684319

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknown1not providednot provided1not providedclinical 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

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]
PMID:
25741868
PMCID:
PMC4544753

Details of each submission

From Ambry Genetics, SCV000185512.6

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical testing PubMed (1)

Description

Other strong data supporting benign classification

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknown1not providednot provided1not providednot providednot provided

From Color Health, Inc, SCV000684319.3

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Sep 26, 2021

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