NM_000179.3(MSH6):c.3724C>A (p.Arg1242Ser) AND Hereditary nonpolyposis colorectal neoplasms

Clinical significance:Likely pathogenic (Last evaluated: Oct 22, 2020)

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
1 submission [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 nonpolyposis colorectal neoplasms
MedGen: C0009405; Orphanet: 443090

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
SCV000551123Invitaecriteria provided, single submitter
Likely pathogenic
(Oct 22, 2020)
germlineclinical testing

PubMed (7)
[See all records that cite these PMIDs]

Summary from all submissions

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



LOVD v.2.0: the next generation in gene variant databases.

Fokkema IF, Taschner PE, Schaafsma GC, Celli J, Laros JF, den Dunnen JT.

Hum Mutat. 2011 May;32(5):557-63. doi: 10.1002/humu.21438. Epub 2011 Feb 22.

PubMed [citation]

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]
See all PubMed Citations (7)

Details of each submission

From Invitae, SCV000551123.6

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (7)


This sequence change replaces arginine with serine at codon 1242 of the MSH6 protein (p.Arg1242Ser). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and serine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individual(s) in the Leiden Open-source Variation Database and in individuals with clinical features of Lynch syndrome, and has been observed to co-occur with MSH6 c.3601C>G (p.Leu1201Val) (PMID: 21520333, 29875428, Invitae). ClinVar contains an entry for this variant (Variation ID: 89449). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant disrupts the p.Arg1242 amino acid residue in MSH6. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 24763289, 23729658, 17718861, 24933100). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

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

Last Updated: Jul 7, 2021

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