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NM_000249.4(MLH1):c.1A>G (p.Met1Val) AND not provided

Germline classification:
Pathogenic (1 submission)
Last evaluated:
Nov 7, 2022
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:
RCV003477467.1

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)

Synonyms:
none provided
Identifiers:
MedGen: C3661900

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV004220864Quest Diagnostics Nichols Institute San Juan Capistrano
criteria provided, single submitter

(Quest Diagnostics criteria)		Pathogenic
(Nov 7, 2022) 		unknownclinical testing

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

Help

Summary from all submissions

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

Citations

PubMed

Hereditary nonpolyposis colorectal cancer (HNPCC): eight novel germline mutations in hMSH2 or hMLH1 genes.

Wehner M, Buschhausen L, Lamberti C, Kruse R, Caspari R, Propping P, Friedl W.

Hum Mutat. 1997;10(3):241-4. No abstract available.

PubMed [citation]
PMID:
9298827

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 Quest Diagnostics Nichols Institute San Juan Capistrano, SCV004220864.1

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

Description

This variant disrupts the translation initiation codon of the MLH1 mRNA and is predicted to interfere with MLH1 protein synthesis. This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In the published literature, the variant has been reported in multiple individuals with MLH1 related disease (PMID: 11112663 (2001), 24302565 (2015), 9298827 (1997)). This variant was also found to reduce protein expression and MMR efficacy (PMID: 24302565 (2015)). Based on the available information, this variant is classified as pathogenic.

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

Last Updated: Aug 11, 2024