NM_000179.3(MSH6):c.3724C>A (p.Arg1242Ser) AND Hereditary cancer-predisposing syndrome

Clinical significance:Likely pathogenic (Last evaluated: Jul 6, 2020)

Review status:2 stars out of maximum of 4 stars

criteria provided, multiple submitters, no conflicts

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]


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

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
SCV000276653Ambry Geneticscriteria provided, single submitter
Likely pathogenic
(Jul 6, 2020)
germlineclinical testing

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

Citation Link,

SCV001344754Color Health, Inccriteria provided, single submitter
Likely pathogenic
(Apr 20, 2020)
germlineclinical testing

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


This missense variant replaces arginine with serine at codon 1242 in the ATPase domain of the MSH6 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). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in cis with c.3601C>G (p.Leu1201Val) in individuals affected with Lynch syndrome-associated cancers (PMID: 29875428, 31391288; O’Leary 2014; Clinvar variation ID: 89449), as well as in an individual affected with constitutional mismatch repair deficiency who carried a pathogenic c.3434-2A>G variant in the different chromosome (Alshuaibi et al., ACMG 2016 poster). This variant has been identified in 1/31406 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Different variants affecting the same amino acid position, p.Arg1242His and p.Arg1242del, are known to be disease-causing (Clinvar variation ID: 140866 and 89450), indicating the importance of arginine at this position for MSH6 protein function. Based on the available evidence, this variant is classified as Likely Pathogenic.


Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknown1not providednot provided1not providedclinical testing



Utilization of multigene panels in hereditary cancer predisposition testing: analysis of more than 2,000 patients.

LaDuca H, Stuenkel AJ, Dolinsky JS, Keiles S, Tandy S, Pesaran T, Chen E, Gau CL, Palmaer E, Shoaepour K, Shah D, Speare V, Gandomi S, Chao E.

Genet Med. 2014 Nov;16(11):830-7. doi: 10.1038/gim.2014.40. Epub 2014 Apr 24.

PubMed [citation]

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]

Details of each submission

From Ambry Genetics, SCV000276653.6

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


The p.R1242S variant (also known as c.3724C>A), located in coding exon 8 of the MSH6 gene, results from a C to A substitution at nucleotide position 3724. The arginine at codon 1242 is replaced by serine, an amino acid with dissimilar properties. The p.L1201V variant (also known as c.3601C>G), located in coding exon 7 of the MSH6 gene, results from a C to G substitution at nucleotide position 3601. The leucine at codon 1201 is replaced by valine, an amino acid with highly similar properties. The p.L1201V and p.R1242S alterations have been observed to be linked in cis and in complete linkage disequilibrium (Ambry internal data). This haplotype has been observed in several individuals diagnosed with Lynch-related tumors in their 40-50s, including individuals who met Amsterdam criteria and with MSI-H colorectal tumors and/or loss of MSH6 on immunohistochemistry (O'Leary et al. Am. J. Digest. Dis. 2014;1(1):62-66; Ambry internal data). This haplotype has also been observed in conjunction with a mutation in MSH6 (c.3439-2A>G), in a girl with clinical features consistent with constitutional mismatch repair deficiency (CMMRD) syndrome (Ambry internal data). Based on internal structural analysis, this haplotype is more destabilizing than known likely pathogenic variants in the same domain. This amino acid position is highly conserved in available vertebrate species. The in silico predictions for p.L1201V and p.R1242S alterations are inconclusive and deleterious, respectively. Based on the majority of available evidence to date, this haplotype is likely to be pathogenic.

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

From Color Health, Inc, SCV001344754.1

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

Last Updated: Jul 7, 2021

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