NM_005236.3(ERCC4):c.1727G>C (p.Arg576Thr) AND not provided

Clinical significance:Uncertain significance

Review status:(0/4) 0 stars out of maximum of 4 stars

no assertion criteria provided

Based on:
3 submissions [Details]
Record status:
current
Accession:
RCV001357601.4

Allele description [Variation Report for NM_005236.3(ERCC4):c.1727G>C (p.Arg576Thr)]

NM_005236.3(ERCC4):c.1727G>C (p.Arg576Thr)

Gene:
ERCC4:ERCC excision repair 4, endonuclease catalytic subunit [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
16p13.12
Genomic location:
Preferred name:
NM_005236.3(ERCC4):c.1727G>C (p.Arg576Thr)
HGVS:
  • NC_000016.10:g.13935659G>C
  • NG_011442.1:g.20503G>C
  • NM_005236.2:c.1727G>C
  • NM_005236.3:c.1727G>CMANE SELECT
  • NP_005227.1:p.Arg576Thr
  • NP_005227.1:p.Arg576Thr
  • LRG_463t1:c.1727G>C
  • LRG_463:g.20503G>C
  • LRG_463p1:p.Arg576Thr
  • NC_000016.9:g.14029516G>C
  • Q92889:p.Arg576Thr
Protein change:
R576T
Links:
UniProtKB: Q92889#VAR_013397; dbSNP: rs1800068
NCBI 1000 Genomes Browser:
rs1800068
Molecular consequence:
  • NM_005236.2:c.1727G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_005236.3:c.1727G>C - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Identifiers:
MedGen: CN517202

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV001553115Department of Pathology and Laboratory Medicine,Sinai Health System - The Canadian Open Genetics Repository (COGR)

See additional submitters

no assertion criteria providedUncertain significanceunknownclinical testing

SCV001742068Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen - VKGL Data-share Consensusno assertion criteria providedUncertain significancegermlineclinical testing

SCV001972335Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center - VKGL Data-share Consensus

See additional submitters

no assertion criteria providedUncertain significancegermlineclinical testing

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineyesnot providednot providednot providednot providednot providedclinical testing
not providedunknownyesnot providednot providednot providednot providednot providedclinical testing

Details of each submission

From Department of Pathology and Laboratory Medicine,Sinai Health System - The Canadian Open Genetics Repository (COGR), SCV001553115.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided

Description

The ERCC4 p.Arg576Thr variant was identified in 10 of 6374 proband chromosomes (frequency: 0.001569) from individuals with breast cancer, colorectal cancer, pancreatic ductal adenocarcinoma or head and neck squamous cell carcinoma and was present in 2 of 154 control chromosomes (frequency: 0.01299) from healthy individuals (McVeigh_2020_PMID:32008151; West_2018; Shindo_2017_PMID:28767289; Chandrasekharappa_2017_PMID:28678401). The variant was identified in dbSNP (ID: rs1800068) and ClinVar (classified as uncertain significance by Invitae). The variant was identified in control databases in 185 of 281516 chromosomes at a frequency of 0.0006572 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: Latino in 45 of 35426 chromosomes (freq: 0.00127), European (non-Finnish) in 126 of 127888 chromosomes (freq: 0.000985), Other in 7 of 7216 chromosomes (freq: 0.00097), African in 5 of 24972 chromosomes (freq: 0.0002) and European (Finnish) in 2 of 25102 chromosomes (freq: 0.00008), but was not observed in the Ashkenazi Jewish, East Asian, or South Asian populations. The p.Arg576 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. Functional assays demonstrated defective DNA repair function after UV-induced DNA damage with ERCC4 p.R576T compared to wildtype (West_2018). In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1unknownyesnot providednot providednot providednot providednot providednot providednot provided

From Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen - VKGL Data-share Consensus, SCV001742068.3

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providednot providednot providednot providednot providednot provided

From Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center - VKGL Data-share Consensus, SCV001972335.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Nov 27, 2021

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