NM_000179.3(MSH6):c.194C>T (p.Ser65Leu) AND Hereditary nonpolyposis colorectal neoplasms

Clinical significance:Uncertain significance (Last evaluated: Oct 20, 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.194C>T (p.Ser65Leu)]

NM_000179.3(MSH6):c.194C>T (p.Ser65Leu)

MSH6:mutS homolog 6 [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
Genomic location:
Preferred name:
NM_000179.3(MSH6):c.194C>T (p.Ser65Leu)
Other names:
  • NC_000002.12:g.47783427C>T
  • NG_007111.1:g.5281C>T
  • NM_000179.2:c.194C>T
  • NM_000179.3:c.194C>TMANE SELECT
  • NM_001281492.2:c.194C>T
  • NM_001281493.2:c.-543C>T
  • NP_000170.1:p.Ser65Leu
  • NP_000170.1:p.Ser65Leu
  • NP_001268421.1:p.Ser65Leu
  • LRG_219t1:c.194C>T
  • LRG_219:g.5281C>T
  • LRG_219p1:p.Ser65Leu
  • NC_000002.11:g.48010566C>T
  • P52701:p.Ser65Leu
Protein change:
UniProtKB: P52701#VAR_038034; dbSNP: rs41294984
NCBI 1000 Genomes Browser:
Molecular consequence:
  • NM_001281493.2:c.-543C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_000179.2:c.194C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_000179.3:c.194C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001281492.2:c.194C>T - 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)
SCV000166215Invitaecriteria provided, single submitter
Uncertain significance
(Oct 20, 2020)
germlineclinical testing

PubMed (5)
[See all records that cite these PMIDs]

Summary from all submissions

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



Classification of ambiguous mutations in DNA mismatch repair genes identified in a population-based study of colorectal cancer.

Barnetson RA, Cartwright N, van Vliet A, Haq N, Drew K, Farrington S, Williams N, Warner J, Campbell H, Porteous ME, Dunlop MG.

Hum Mutat. 2008 Mar;29(3):367-74.

PubMed [citation]

Germline variation in cancer-susceptibility genes in a healthy, ancestrally diverse cohort: implications for individual genome sequencing.

Bodian DL, McCutcheon JN, Kothiyal P, Huddleston KC, Iyer RK, Vockley JG, Niederhuber JE.

PLoS One. 2014;9(4):e94554. doi: 10.1371/journal.pone.0094554.

PubMed [citation]
See all PubMed Citations (5)

Details of each submission

From Invitae, SCV000166215.7

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (5)


This sequence change replaces serine with leucine at codon 65 of the MSH6 protein (p.Ser65Leu). The serine residue is weakly conserved and there is a large physicochemical difference between serine and leucine. This variant is present in population databases (rs41294984, ExAC 0.02%). This variant has been reported in individuals affected with colorectal cancer (PMID: 18033691), as well as in healthy control individuals (PMID: 24728327). ClinVar contains an entry for this variant (Variation ID: 89234). 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 tolerated, but these predictions have not been confirmed by published functional studies. Furthermore, algorithms developed to predict the effect of missense changes in mismatch repair genes both predict that this variant is neutral (PMID: 22290698, 23621914). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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

Last Updated: Nov 27, 2021

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