NM_000251.3(MSH2):c.182A>C (p.Gln61Pro) AND Hereditary cancer-predisposing syndrome

Clinical significance:Conflicting interpretations of pathogenicity, Likely benign(1);Uncertain significance(2) (Last evaluated: Jul 22, 2020)

Review status:1 star out of maximum of 4 stars

criteria provided, conflicting interpretations

Based on:
3 submissions [Details]
Record status:
current
Accession:
RCV000708715.6

Allele description [Variation Report for NM_000251.3(MSH2):c.182A>C (p.Gln61Pro)]

NM_000251.3(MSH2):c.182A>C (p.Gln61Pro)

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.182A>C (p.Gln61Pro)
HGVS:
  • NC_000002.12:g.47403373A>C
  • NG_007110.2:g.5250A>C
  • NM_000251.2:c.182A>C
  • NM_000251.3:c.182A>CMANE SELECT
  • NM_001258281.1:c.-17A>C
  • NP_000242.1:p.Gln61Pro
  • NP_000242.1:p.Gln61Pro
  • LRG_218t1:c.182A>C
  • LRG_218:g.5250A>C
  • LRG_218p1:p.Gln61Pro
  • NC_000002.11:g.47630512A>C
  • NM_000251.1:c.182A>C
Protein change:
Q61P
Links:
dbSNP: rs587779113
NCBI 1000 Genomes Browser:
rs587779113
Molecular consequence:
  • NM_001258281.1:c.-17A>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_000251.2:c.182A>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_000251.3:c.182A>C - 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
SCV000822049GeneKor MSAcriteria provided, single submitter
Uncertain significance
(Aug 1, 2018)
germlineclinical testing

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

SCV000908272Color Health, Inccriteria provided, single submitter
Uncertain significance
(Jul 22, 2020)
germlineclinical testing

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

SCV001173915Ambry Geneticscriteria provided, single submitter
Likely benign
(Mar 4, 2020)
germlineclinical testing

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

Citation Link

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineyesnot providednot providednot providednot providednot providedclinical testing
not providedgermlineunknown1not providednot provided1not providedclinical testing

Citations

PubMed

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

Structure of the human MutSalpha DNA lesion recognition complex.

Warren JJ, Pohlhaus TJ, Changela A, Iyer RR, Modrich PL, Beese LS.

Mol Cell. 2007 May 25;26(4):579-92.

PubMed [citation]
PMID:
17531815
See all PubMed Citations (3)

Details of each submission

From GeneKor MSA, SCV000822049.1

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

From Color Health, Inc, SCV000908272.3

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

Description

This missense variant replaces glutamine with proline at codon 61 of the MSH2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. Experimental studies have reported this variant protein to be functional in yeast mutator and protein binding assays (PMID: 17720936, 20176959). This variant has been reported in an individual affected with ovarian and colorectal cancer (PMID: 25133505). This variant has been identified in 1/232376 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.

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

From Ambry Genetics, SCV001173915.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical testing PubMed (2)

Description

In silico models in agreement (benign);Other data supporting benign classification

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

Last Updated: Nov 20, 2021

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