U.S. flag

An official website of the United States government

NM_000249.4(MLH1):c.104T>G (p.Met35Arg) AND Hereditary cancer-predisposing syndrome

Germline classification:
Pathogenic (1 submission)
Last evaluated:
Nov 13, 2017
Review status:
1 star out of maximum of 4 stars
criteria provided, single submitter
Somatic classification
of clinical impact:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Somatic classification
of oncogenicity:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Record status:
current
Accession:
RCV002399429.1

Allele description

NM_000249.4(MLH1):c.104T>G (p.Met35Arg)

Gene:
MLH1:mutL homolog 1 [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
3p22.2
Genomic location:
Preferred name:
NM_000249.4(MLH1):c.104T>G (p.Met35Arg)
HGVS:
  • NC_000003.12:g.36993651T>G
  • NG_007109.2:g.5302T>G
  • NG_008418.1:g.4654A>C
  • NM_000249.4:c.104T>GMANE SELECT
  • NM_001167617.3:c.-413T>G
  • NM_001167618.3:c.-842T>G
  • NM_001167619.3:c.-755T>G
  • NM_001258271.2:c.104T>G
  • NM_001258273.2:c.-529T>G
  • NM_001258274.3:c.-992T>G
  • NM_001354615.2:c.-523T>G
  • NM_001354616.2:c.-523T>G
  • NM_001354617.2:c.-615T>G
  • NM_001354618.2:c.-847T>G
  • NM_001354619.2:c.-971T>G
  • NM_001354620.2:c.-181T>G
  • NM_001354621.2:c.-940T>G
  • NM_001354622.2:c.-1053T>G
  • NM_001354623.2:c.-962T>G
  • NM_001354624.2:c.-723T>G
  • NM_001354625.2:c.-621T>G
  • NM_001354626.2:c.-718T>G
  • NM_001354627.2:c.-950T>G
  • NM_001354628.2:c.104T>G
  • NM_001354629.2:c.104T>G
  • NM_001354630.2:c.104T>G
  • NP_000240.1:p.Met35Arg
  • NP_000240.1:p.Met35Arg
  • NP_001245200.1:p.Met35Arg
  • NP_001341557.1:p.Met35Arg
  • NP_001341558.1:p.Met35Arg
  • NP_001341559.1:p.Met35Arg
  • LRG_216t1:c.104T>G
  • LRG_216:g.5302T>G
  • LRG_216p1:p.Met35Arg
  • NC_000003.11:g.37035142T>G
  • NM_000249.3:c.104T>G
  • P40692:p.Met35Arg
Protein change:
M35R
Links:
UniProtKB: P40692#VAR_004434; dbSNP: rs63749906
NCBI 1000 Genomes Browser:
rs63749906
Molecular consequence:
  • NM_001167617.3:c.-413T>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001167618.3:c.-842T>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001167619.3:c.-755T>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001258273.2:c.-529T>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001258274.3:c.-992T>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001354615.2:c.-523T>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001354616.2:c.-523T>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001354617.2:c.-615T>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001354618.2:c.-847T>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001354619.2:c.-971T>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001354620.2:c.-181T>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001354621.2:c.-940T>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001354622.2:c.-1053T>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001354623.2:c.-962T>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001354624.2:c.-723T>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001354625.2:c.-621T>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001354626.2:c.-718T>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001354627.2:c.-950T>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_000249.4:c.104T>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001258271.2:c.104T>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354628.2:c.104T>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354629.2:c.104T>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354630.2:c.104T>G - missense variant - [Sequence Ontology: SO:0001583]
Observations:
1

Condition(s)

Name:
Hereditary cancer-predisposing syndrome
Synonyms:
Neoplastic Syndromes, Hereditary; Tumor predisposition; Cancer predisposition; See all synonyms [MedGen]
Identifiers:
MONDO: MONDO:0015356; MeSH: D009386; MedGen: C0027672

Recent activity

Clear Turn Off Turn On

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...

Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV002706079Ambry Genetics
criteria provided, single submitter

(Ambry General Variant Classification Scheme_2022)		Pathogenic
(Nov 13, 2017) 		germlineclinical testing

PubMed (6)
[See all records that cite these PMIDs]

Citation Link

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknown1not providednot provided1not providedclinical testing

Citations

PubMed

Mutator phenotypes conferred by MLH1 overexpression and by heterozygosity for mlh1 mutations.

Shcherbakova PV, Kunkel TA.

Mol Cell Biol. 1999 Apr;19(4):3177-83.

PubMed [citation]
PMID:
10082584
PMCID:
PMC84111

A yeast two-hybrid assay provides a simple way to evaluate the vast majority of hMLH1 germ-line mutations.

Kondo E, Suzuki H, Horii A, Fukushige S.

Cancer Res. 2003 Jun 15;63(12):3302-8.

PubMed [citation]
PMID:
12810663
See all PubMed Citations (6)

Details of each submission

From Ambry Genetics, SCV002706079.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical testing PubMed (6)

Description

The p.M35R pathogenic mutation (also known as c.104T>G), located in coding exon 1 of the MLH1 gene, results from a T to G substitution at nucleotide position 104. The methionine at codon 35 is replaced by arginine, an amino acid with similar properties. This amino acid position is well conserved in available vertebrate species. This mutation, designated Met35>Arg (ATG>AGG), segregated with disease in a Swedish family meeting Amsterdam criteria (Tannergård P et al. Cancer Res. 1995 Dec;55:6092-6) and was identified in an individual with HNPCC whose two adenomas with low grade dysplasia demonstrated absent MLH1 and PMS2 by immunohistochemistry (Halvarsson B et al. Mod. Pathol. 2005 Aug;18:1095-101). In yeast functional assays, the M35R variant showed a mutator phenotype when compared to wild type suggesting inactivation of mismatch repair (Shcherbakova PV et al. Mol. Cell. Biol. 1999 Apr;19:3177-83). In a yeast two-hybrid assay, M35R displayed almost no beta-galactosidase activity similar to known deleterious alterations (Kondo E et al. Cancer Res. 2003 Jun;63:3302-8). Additionally, the M35R variant demonstrated no dominant mutator effect in reporter assays in yeast, which is consistent with pathogenicity (Shimodaira H et al. Nat Genet. 1998 Aug;19(4):384-9; Takahashi M et al. Cancer Res. 2007 May;67:4595-604). This alteration has been classified as pathogenic using the following lines of evidence: in silico prediction models, segregation with disease, clinical phenotype including tumor characteristics, mutation co-occurrence, and functional studies (Thompson BA et al. Hum. Mutat. 2013 Jan;34:200-9; Thompson BA et al. Nat. Genet. 2014 Feb;46:107-15; available at [www.insight-group.org/variants/classifications/]). In addition, the in silico prediction for this alteration is inconclusive. In addition, this alteration is predicted to be deleterious by MAPP-MMR in silico analyses (Chao EC et al. Hum. Mutat. 2008 Jun;29:852-60). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.

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

Last Updated: Feb 4, 2024