NM_000179.3(MSH6):c.3724C>A (p.Arg1242Ser) AND not provided

Clinical significance:Conflicting interpretations of pathogenicity, Likely pathogenic(1);Uncertain significance(1) (Last evaluated: Oct 25, 2018)

Review status:1 star out of maximum of 4 stars

criteria provided, conflicting interpretations

Based on:
2 submissions [Details]
Record status:

Allele description [Variation Report for NM_000179.3(MSH6):c.3724C>A (p.Arg1242Ser)]

NM_000179.3(MSH6):c.3724C>A (p.Arg1242Ser)

MSH6:mutS homolog 6 [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
Genomic location:
Preferred name:
NM_000179.3(MSH6):c.3724C>A (p.Arg1242Ser)
  • NC_000002.12:g.47806281C>A
  • NG_007111.1:g.28135C>A
  • NG_008397.1:g.104395G>T
  • NM_000179.2:c.3724C>A
  • NM_000179.3:c.3724C>AMANE SELECT
  • NM_001281492.1:c.3334C>A
  • NM_001281493.1:c.2818C>A
  • NM_001281494.1:c.2818C>A
  • NP_000170.1:p.Arg1242Ser
  • NP_000170.1:p.Arg1242Ser
  • NP_001268421.1:p.Arg1112Ser
  • NP_001268422.1:p.Arg940Ser
  • NP_001268423.1:p.Arg940Ser
  • LRG_219t1:c.3724C>A
  • LRG_219:g.28135C>A
  • LRG_219p1:p.Arg1242Ser
  • NC_000002.11:g.48033420C>A
Protein change:
dbSNP: rs587779285
NCBI 1000 Genomes Browser:
Molecular consequence:
  • NM_000179.2:c.3724C>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_000179.3:c.3724C>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001281492.1:c.3334C>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001281493.1:c.2818C>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001281494.1:c.2818C>A - missense variant - [Sequence Ontology: SO:0001583]


MedGen: CN517202

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
SCV000565850GeneDxcriteria provided, single submitter
Likely pathogenic
(Jul 25, 2018)
germlineclinical testing

Citation Link,

SCV001134439Quest Diagnostics Nichols Institute San Juan Capistranocriteria provided, single submitter
Uncertain significance
(Oct 25, 2018)
germlineclinical testing

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

Summary from all submissions

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



The impact of variant classification on the clinical management of hereditary cancer syndromes.

Turner SA, Rao SK, Morgan RH, Vnencak-Jones CL, Wiesner GL.

Genet Med. 2019 Feb;21(2):426-430. doi: 10.1038/s41436-018-0063-z. Epub 2018 Jun 6.

PubMed [citation]

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]

Details of each submission

From GeneDx, SCV000565850.4

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


This variant is denoted MSH6 c.3724C>A at the cDNA level, p.Arg1242Ser (R1242S) at the protein level, and results in the change of an Arginine to a Serine (CGT>AGT). This variant has been identified in at least two individuals with a personal and/or family history of colon cancer, with both individuals also carrying the MSH6 Leu1201Val variant (O?Leary 2014, Turner 2018). Of note, a different variant at the same residue, Arg1242His, has been observed in the homozygous state in two brothers with features of CMMRD (Grandaval 2013). In addition, a deletion of the Arg1242 residue (p.Arg1242del) has been reported in individuals with colorectal or uterine cancer demonstrating loss of MSH6 protein on immunohistochemistry (IHC) (Roncari 2007, Batte 2014). MSH6 Arg1242Ser was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the ATPase domain (Warren 2007, Kansikas 2011). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, we consider MSH6 Arg1242Ser to be a likely pathogenic variant.

OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providednot providednot providednot providednot providednot provided

From Quest Diagnostics Nichols Institute San Juan Capistrano, SCV001134439.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (2)
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Jul 7, 2021

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