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NM_000249.4(MLH1):c.1A>G (p.Met1Val) AND Hereditary cancer-predisposing syndrome

Germline classification:
Pathogenic (1 submission)
Last evaluated:
Jun 20, 2024
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:
RCV002415530.3

Allele description [Variation Report for NM_000249.4(MLH1):c.1A>G (p.Met1Val)]

NM_000249.4(MLH1):c.1A>G (p.Met1Val)

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.1A>G (p.Met1Val)
HGVS:
  • NC_000003.12:g.36993548A>G
  • NG_007109.2:g.5199A>G
  • NG_008418.1:g.4757T>C
  • NM_000249.4:c.1A>GMANE SELECT
  • NM_001167617.3:c.-516A>G
  • NM_001167618.3:c.-945A>G
  • NM_001167619.3:c.-858A>G
  • NM_001258271.2:c.1A>G
  • NM_001258273.2:c.-632A>G
  • NM_001258274.3:c.-1095A>G
  • NM_001354615.2:c.-626A>G
  • NM_001354616.2:c.-626A>G
  • NM_001354617.2:c.-718A>G
  • NM_001354618.2:c.-950A>G
  • NM_001354619.2:c.-1074A>G
  • NM_001354620.2:c.-284A>G
  • NM_001354621.2:c.-1043A>G
  • NM_001354622.2:c.-1156A>G
  • NM_001354623.2:c.-1065A>G
  • NM_001354624.2:c.-826A>G
  • NM_001354625.2:c.-724A>G
  • NM_001354626.2:c.-821A>G
  • NM_001354627.2:c.-1053A>G
  • NM_001354628.2:c.1A>G
  • NM_001354629.2:c.1A>G
  • NM_001354630.2:c.1A>G
  • NP_000240.1:p.Met1Val
  • NP_000240.1:p.Met1Val
  • NP_001245200.1:p.Met1Val
  • NP_001341557.1:p.Met1Val
  • NP_001341558.1:p.Met1Val
  • NP_001341559.1:p.Met1Val
  • LRG_216t1:c.1A>G
  • LRG_216:g.5199A>G
  • LRG_216p1:p.Met1Val
  • NC_000003.11:g.37035039A>G
  • NM_000249.3:c.1A>G
Protein change:
M1V
Links:
dbSNP: rs587778967
NCBI 1000 Genomes Browser:
rs587778967
Molecular consequence:
  • NM_001167617.3:c.-516A>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001167618.3:c.-945A>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001167619.3:c.-858A>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001258273.2:c.-632A>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001258274.3:c.-1095A>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001354615.2:c.-626A>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001354616.2:c.-626A>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001354617.2:c.-718A>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001354618.2:c.-950A>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001354619.2:c.-1074A>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001354620.2:c.-284A>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001354621.2:c.-1043A>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001354622.2:c.-1156A>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001354623.2:c.-1065A>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001354624.2:c.-826A>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001354625.2:c.-724A>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001354626.2:c.-821A>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001354627.2:c.-1053A>G - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_000249.4:c.1A>G - initiator_codon_variant - [Sequence Ontology: SO:0001582]
  • NM_001258271.2:c.1A>G - initiator_codon_variant - [Sequence Ontology: SO:0001582]
  • NM_001354628.2:c.1A>G - initiator_codon_variant - [Sequence Ontology: SO:0001582]
  • NM_001354629.2:c.1A>G - initiator_codon_variant - [Sequence Ontology: SO:0001582]
  • NM_001354630.2:c.1A>G - initiator_codon_variant - [Sequence Ontology: SO:0001582]
  • NM_000249.4:c.1A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001258271.2:c.1A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354628.2:c.1A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354629.2:c.1A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354630.2:c.1A>G - missense variant - [Sequence Ontology: SO:0001583]

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

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV002721813Ambry Genetics
criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)		Pathogenic
(Jun 20, 2024) 		germlineclinical testing

PubMed (4)
[See all records that cite these PMIDs]

Citation Link

Help

Summary from all submissions

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

Citations

PubMed

Hereditary nonpolyposis colorectal cancer in 95 families: differences and similarities between mutation-positive and mutation-negative kindreds.

Scott RJ, McPhillips M, Meldrum CJ, Fitzgerald PE, Adams K, Spigelman AD, du Sart D, Tucker K, Kirk J.

Am J Hum Genet. 2001 Jan;68(1):118-127. Epub 2000 Dec 7. Erratum in: Am J Hum Genet 2001 Feb;68(2):557.

PubMed [citation]
PMID:
11112663
PMCID:
PMC1234904

Consequences of germline variation disrupting the constitutional translational initiation codon start sites of MLH1 and BRCA2: Use of potential alternative start sites and implications for predicting variant pathogenicity.

Parsons MT, Whiley PJ, Beesley J, Drost M, de Wind N, Thompson BA, Marquart L, Hopper JL, Jenkins MA; Australasian Colorectal Cancer Family Registry., Brown MA, Tucker K, Warwick L, Buchanan DD, Spurdle AB.

Mol Carcinog. 2015 Jul;54(7):513-22. doi: 10.1002/mc.22116. Epub 2013 Dec 2.

PubMed [citation]
PMID:
24302565
PMCID:
PMC4041856
See all PubMed Citations (4)

Details of each submission

From Ambry Genetics, SCV002721813.4

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (4)

Description

The p.M1? pathogenic mutation (also known as c.1A>G) is located in coding exon 1 of the MLH1 gene and results from an A to G substitution at nucleotide position 1. This alters the methionine residue at the initiation codon (ATG). The N-terminus of MLH1 is known to be functionally and structurally important (Ambry internal analysis; Tempel W et al. Structural Genomics Consortium. PDB ID: 4P7A Crystal Structure of human MLH1). One functional assay demonstrated that the c.1A>G allele encodes an in-frame protein lacking the first 34 amino acids resulting in deficient mismatch repair activity similar to that of a known pathogenic missense alteration (Parsons MT et al. Mol. Carcinog. 2015 Jul;54:513-22). Additionally, this mutation has been reported in several individuals with HNPCC (Scott RJ et al. Am. J. Hum. Genet. 2001 Jan;68:118-127; Sjursen W et al. Mol Genet Genomic Med, 2016 Mar;4:223-31), including an individual meeting Amsterdam criteria (Parsons MT et al. Mol. Carcinog., 2015 Jul;54:513-22). This mutation has been identified in conjunction with MLH1 loss of heterozygosity (LOH) in an MMR deficient tumor, supporting pathogenicity (Shirts BH et al. Am. J. Hum. Genet. 2018 Jul;103:19-29). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition to the clinical data presented in the literature, sequence variations that modify the initiation codon are expected to result in either loss of translation initiation, N-terminal truncation, or cause a shift in the mRNA reading frame. Based on the supporting evidence, this variant is interpreted as a disease-causing mutation.

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

Last Updated: Sep 29, 2024