NM_000251.3(MSH2):c.2211-6C>A AND not specified

Clinical significance:Conflicting interpretations of pathogenicity, Likely benign(1);Uncertain significance(1) (Last evaluated: Feb 1, 2021)

Review status:1 star out of maximum of 4 stars

criteria provided, conflicting interpretations

Based on:
2 submissions [Details]
Record status:
current
Accession:
RCV000236903.4

Allele description [Variation Report for NM_000251.3(MSH2):c.2211-6C>A]

NM_000251.3(MSH2):c.2211-6C>A

Gene:
MSH2:mutS homolog 2 [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
2p21
Genomic location:
Preferred name:
NM_000251.3(MSH2):c.2211-6C>A
HGVS:
  • NC_000002.12:g.47478266C>A
  • NG_007110.2:g.80143C>A
  • NM_000251.3:c.2211-6C>AMANE SELECT
  • NM_001258281.1:c.2013-6C>A
  • LRG_218t1:c.2211-6C>A
  • LRG_218:g.80143C>A
  • NC_000002.11:g.47705405C>A
  • NM_000251.1:c.2211-6C>A
  • NM_000251.2:c.2211-6C>A
Links:
dbSNP: rs267608003
NCBI 1000 Genomes Browser:
rs267608003
Molecular consequence:
  • NM_000251.3:c.2211-6C>A - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001258281.1:c.2013-6C>A - intron variant - [Sequence Ontology: SO:0001627]

Condition(s)

Synonyms:
AllHighlyPenetrant
Identifiers:
MedGen: CN169374

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000601461Quest Diagnostics Nichols Institute San Juan Capistranocriteria provided, single submitter
Uncertain significance
(Jan 15, 2017)
germlineclinical testing

PubMed (3)
[See all records that cite these PMIDs]

SCV000696241Women's Health and Genetics/Laboratory Corporation of America, LabCorpcriteria provided, single submitter
Likely benign
(Feb 1, 2021)
germlineclinical testing

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

Citation Link

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

A Standardized DNA Variant Scoring System for Pathogenicity Assessments in Mendelian Disorders.

Karbassi I, Maston GA, Love A, DiVincenzo C, Braastad CD, Elzinga CD, Bright AR, Previte D, Zhang K, Rowland CM, McCarthy M, Lapierre JL, Dubois F, Medeiros KA, Batish SD, Jones J, Liaquat K, Hoffman CA, Jaremko M, Wang Z, Sun W, Buller-Burckle A, et al.

Hum Mutat. 2016 Jan;37(1):127-34. doi: 10.1002/humu.22918. Epub 2015 Oct 29.

PubMed [citation]
PMID:
26467025
PMCID:
PMC4737317

Use of panel tests in place of single gene tests in the cancer genetics clinic.

Yorczyk A, Robinson LS, Ross TS.

Clin Genet. 2015 Sep;88(3):278-82. doi: 10.1111/cge.12488. Epub 2014 Oct 16.

PubMed [citation]
PMID:
25318351
See all PubMed Citations (3)

Details of each submission

From Quest Diagnostics Nichols Institute San Juan Capistrano, SCV000601461.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (3)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000696241.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (2)

Description

Variant summary: MSH2 c.2211-6C>A alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by published peer-reviewed functional studies. The UMD database cites the variant in 1 individual with a classification of UV and indicates that the variant affects splicing, however, a traceable functional evidence is not provided. The variant allele was found at a frequency of 0.0001 in 251186 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in MSH2 causing Hereditary Nonpolyposis Colorectal Cancer/Lynch syndrome (0.0001 vs 0.00057), allowing no conclusion about variant significance. c.2211-6C>A has been reported in the literature in individuals undergoing multigene panel testing for cancer (example, Kraus_2015, Yorcyzk_2015). One of these studies reported this variant as being observed in an affected male that fulfilled the revised Bethesda criteria, had a normal IHC staining, and whose tumor sequencing identified 2 nonsense mutations in the APC gene (Kraus_2015). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Nonpolyposis Colorectal Cancer/Lynch syndrome. At-least one co-occurrence with another pathogenic variant(s) has been ascertained in the context of this evaluation (MLH1 c.1846_1848AAG , p.Lys618del, Keinath_2011, unpublished PhD thesis), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (likely benign, n=2; VUS, n=5). Some submitters cite overlapping references utilized in the context of this evaluation. Based on the preponderance of evidence supporting a neutral outcome as outlined above, the variant was re-classified as likely benign.

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

Last Updated: Nov 27, 2021

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