NM_000249.4(MLH1):c.1032del (p.Phe344fs) AND Hereditary nonpolyposis colorectal neoplasms

Clinical significance:Pathogenic (Last evaluated: Sep 24, 2019)

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.1032del (p.Phe344fs)]

NM_000249.4(MLH1):c.1032del (p.Phe344fs)

MLH1:mutL homolog 1 [Gene - OMIM - HGNC]
Variant type:
Cytogenetic location:
Genomic location:
Preferred name:
NM_000249.4(MLH1):c.1032del (p.Phe344fs)
  • NC_000003.12:g.37020457del
  • NG_007109.2:g.32108del
  • NM_000249.4:c.1032delMANE SELECT
  • NM_001167617.3:c.738del
  • NM_001167618.3:c.309del
  • NM_001167619.3:c.309del
  • NM_001258271.2:c.1032del
  • NM_001258273.2:c.309del
  • NM_001258274.3:c.309del
  • NM_001354615.2:c.309del
  • NM_001354616.2:c.309del
  • NM_001354617.2:c.309del
  • NM_001354618.2:c.309del
  • NM_001354619.2:c.309del
  • NM_001354620.2:c.738del
  • NM_001354621.2:c.9del
  • NM_001354622.2:c.9del
  • NM_001354623.2:c.9del
  • NM_001354624.2:c.-36-5180del
  • NM_001354625.2:c.-36-5180del
  • NM_001354626.2:c.-36-5180del
  • NM_001354627.2:c.-36-5180del
  • NM_001354628.2:c.1032del
  • NM_001354629.2:c.933del
  • NM_001354630.2:c.1032del
  • NP_000240.1:p.Phe344fs
  • NP_001161089.1:p.Phe246fs
  • NP_001161090.1:p.Phe103fs
  • NP_001161091.1:p.Phe103fs
  • NP_001245200.1:p.Phe344fs
  • NP_001245202.1:p.Phe103fs
  • NP_001245203.1:p.Phe103fs
  • NP_001341544.1:p.Phe103fs
  • NP_001341545.1:p.Phe103fs
  • NP_001341546.1:p.Phe103fs
  • NP_001341547.1:p.Phe103fs
  • NP_001341548.1:p.Phe103fs
  • NP_001341549.1:p.Phe246fs
  • NP_001341550.1:p.Phe3fs
  • NP_001341551.1:p.Phe3fs
  • NP_001341552.1:p.Phe3fs
  • NP_001341557.1:p.Phe344fs
  • NP_001341558.1:p.Phe311fs
  • NP_001341559.1:p.Phe344fs
  • LRG_216:g.32108del
  • NC_000003.11:g.37061948del
  • NM_000249.3:c.1032delC
  • p.Phe344Leufs*23
Protein change:
dbSNP: rs1553648225
NCBI 1000 Genomes Browser:
Molecular consequence:
  • NM_000249.4:c.1032del - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_001167617.3:c.738del - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_001167618.3:c.309del - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_001167619.3:c.309del - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_001258271.2:c.1032del - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_001258273.2:c.309del - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_001258274.3:c.309del - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_001354615.2:c.309del - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_001354616.2:c.309del - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_001354617.2:c.309del - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_001354618.2:c.309del - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_001354619.2:c.309del - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_001354620.2:c.738del - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_001354621.2:c.9del - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_001354622.2:c.9del - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_001354623.2:c.9del - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_001354628.2:c.1032del - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_001354629.2:c.933del - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_001354630.2:c.1032del - frameshift variant - [Sequence Ontology: SO:0001589]
  • NM_001354624.2:c.-36-5180del - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001354625.2:c.-36-5180del - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001354626.2:c.-36-5180del - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001354627.2:c.-36-5180del - intron variant - [Sequence Ontology: SO:0001627]


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)
SCV001377549Invitaecriteria provided, single submitter
(Sep 24, 2019)
germlineclinical testing

PubMed (3)
[See all records that cite these PMIDs]

Summary from all submissions

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



Conversion analysis for mutation detection in MLH1 and MSH2 in patients with colorectal cancer.

Casey G, Lindor NM, Papadopoulos N, Thibodeau SN, Moskow J, Steelman S, Buzin CH, Sommer SS, Collins CE, Butz M, Aronson M, Gallinger S, Barker MA, Young JP, Jass JR, Hopper JL, Diep A, Bapat B, Salem M, Seminara D, Haile R; Colon Cancer Family Registry..

JAMA. 2005 Feb 16;293(7):799-809.

PubMed [citation]

Application of a 5-tiered scheme for standardized classification of 2,360 unique mismatch repair gene variants in the InSiGHT locus-specific database.

Thompson BA, Spurdle AB, Plazzer JP, Greenblatt MS, Akagi K, Al-Mulla F, Bapat B, Bernstein I, Capellá G, den Dunnen JT, du Sart D, Fabre A, Farrell MP, Farrington SM, Frayling IM, Frebourg T, Goldgar DE, Heinen CD, Holinski-Feder E, Kohonen-Corish M, Robinson KL, Leung SY, et al.

Nat Genet. 2014 Feb;46(2):107-115. doi: 10.1038/ng.2854. Epub 2013 Dec 22.

PubMed [citation]
See all PubMed Citations (3)

Details of each submission

From Invitae, SCV001377549.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (3)


This sequence change creates a premature translational stop signal (p.Phe344Leufs*23) in the MLH1 gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with MLH1-related conditions. ClinVar contains an entry for this variant (Variation ID: 492681). Loss-of-function variants in MLH1 are known to be pathogenic (PMID: 15713769, 24362816). For these reasons, this variant has been classified as Pathogenic.

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

Last Updated: Dec 2, 2021

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