NM_000249.4(MLH1):c.925C>T (p.Pro309Ser) AND Hereditary nonpolyposis colorectal neoplasms

Clinical significance:Uncertain significance (Last evaluated: Oct 1, 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_000249.4(MLH1):c.925C>T (p.Pro309Ser)]

NM_000249.4(MLH1):c.925C>T (p.Pro309Ser)

MLH1:mutL homolog 1 [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
Genomic location:
Preferred name:
NM_000249.4(MLH1):c.925C>T (p.Pro309Ser)
  • NC_000003.12:g.37020350C>T
  • NG_007109.2:g.32001C>T
  • NM_000249.4:c.925C>TMANE SELECT
  • NM_001167617.3:c.631C>T
  • NM_001167618.3:c.202C>T
  • NM_001167619.3:c.202C>T
  • NM_001258271.2:c.925C>T
  • NM_001258273.2:c.202C>T
  • NM_001258274.3:c.202C>T
  • NM_001354615.2:c.202C>T
  • NM_001354616.2:c.202C>T
  • NM_001354617.2:c.202C>T
  • NM_001354618.2:c.202C>T
  • NM_001354619.2:c.202C>T
  • NM_001354620.2:c.631C>T
  • NM_001354621.2:c.-99C>T
  • NM_001354622.2:c.-99C>T
  • NM_001354623.2:c.-99C>T
  • NM_001354624.2:c.-36-5287C>T
  • NM_001354625.2:c.-36-5287C>T
  • NM_001354626.2:c.-36-5287C>T
  • NM_001354627.2:c.-36-5287C>T
  • NM_001354628.2:c.925C>T
  • NM_001354629.2:c.826C>T
  • NM_001354630.2:c.925C>T
  • NP_000240.1:p.Pro309Ser
  • NP_000240.1:p.Pro309Ser
  • NP_001161089.1:p.Pro211Ser
  • NP_001161090.1:p.Pro68Ser
  • NP_001161091.1:p.Pro68Ser
  • NP_001245200.1:p.Pro309Ser
  • NP_001245202.1:p.Pro68Ser
  • NP_001245203.1:p.Pro68Ser
  • NP_001341544.1:p.Pro68Ser
  • NP_001341545.1:p.Pro68Ser
  • NP_001341546.1:p.Pro68Ser
  • NP_001341547.1:p.Pro68Ser
  • NP_001341548.1:p.Pro68Ser
  • NP_001341549.1:p.Pro211Ser
  • NP_001341557.1:p.Pro309Ser
  • NP_001341558.1:p.Pro276Ser
  • NP_001341559.1:p.Pro309Ser
  • LRG_216t1:c.925C>T
  • LRG_216:g.32001C>T
  • LRG_216p1:p.Pro309Ser
  • NC_000003.11:g.37061841C>T
  • NM_000249.3:c.925C>T
  • P40692:p.Pro309Ser
Protein change:
UniProtKB: P40692#VAR_038025; dbSNP: rs267607808
NCBI 1000 Genomes Browser:
Molecular consequence:
  • NM_001354621.2:c.-99C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001354622.2:c.-99C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001354623.2:c.-99C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001354624.2:c.-36-5287C>T - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001354625.2:c.-36-5287C>T - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001354626.2:c.-36-5287C>T - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001354627.2:c.-36-5287C>T - intron variant - [Sequence Ontology: SO:0001627]
  • NM_000249.4:c.925C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001167617.3:c.631C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001167618.3:c.202C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001167619.3:c.202C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001258271.2:c.925C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001258273.2:c.202C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001258274.3:c.202C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354615.2:c.202C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354616.2:c.202C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354617.2:c.202C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354618.2:c.202C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354619.2:c.202C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354620.2:c.631C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354628.2:c.925C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354629.2:c.826C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354630.2:c.925C>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)
SCV000259481Invitaecriteria provided, single submitter
Uncertain significance
(Oct 1, 2020)
germlineclinical testing

PubMed (2)
[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]

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240-242.

PubMed [citation]

Details of each submission

From Invitae, SCV000259481.5

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


This sequence change replaces proline with serine at codon 309 of the MLH1 protein (p.Pro309Ser). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and serine. This variant is present in population databases (rs267607808, ExAC 0.006%). This variant has been observed in an individual affected with colon cancer (PMID: 18033691). ClinVar contains an entry for this variant (Variation ID: 90444). 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. 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: Dec 4, 2021

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