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NM_000249.4(MLH1):c.170A>C (p.Lys57Thr) AND Lynch syndrome

Germline classification:
Uncertain significance (1 submission)
Last evaluated:
Aug 14, 2023
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:
RCV003997262.2

Allele description [Variation Report for NM_000249.4(MLH1):c.170A>C (p.Lys57Thr)]

NM_000249.4(MLH1):c.170A>C (p.Lys57Thr)

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.170A>C (p.Lys57Thr)
Other names:
p.K57T:AAG>ACG
HGVS:
  • NC_000003.12:g.36996672A>C
  • NG_007109.2:g.8323A>C
  • NG_008418.1:g.1633T>G
  • NM_000249.4:c.170A>CMANE SELECT
  • NM_001167617.3:c.-120A>C
  • NM_001167618.3:c.-554A>C
  • NM_001167619.3:c.-462A>C
  • NM_001258271.2:c.170A>C
  • NM_001258273.2:c.-517+3009A>C
  • NM_001258274.3:c.-699A>C
  • NM_001354615.2:c.-457A>C
  • NM_001354616.2:c.-462A>C
  • NM_001354617.2:c.-554A>C
  • NM_001354618.2:c.-554A>C
  • NM_001354619.2:c.-554A>C
  • NM_001354620.2:c.-120A>C
  • NM_001354621.2:c.-647A>C
  • NM_001354622.2:c.-760A>C
  • NM_001354623.2:c.-723+2782A>C
  • NM_001354624.2:c.-657A>C
  • NM_001354625.2:c.-560A>C
  • NM_001354626.2:c.-657A>C
  • NM_001354627.2:c.-657A>C
  • NM_001354628.2:c.170A>C
  • NM_001354629.2:c.170A>C
  • NM_001354630.2:c.170A>C
  • NP_000240.1:p.Lys57Thr
  • NP_000240.1:p.Lys57Thr
  • NP_001245200.1:p.Lys57Thr
  • NP_001341557.1:p.Lys57Thr
  • NP_001341558.1:p.Lys57Thr
  • NP_001341559.1:p.Lys57Thr
  • LRG_216t1:c.170A>C
  • LRG_216:g.8323A>C
  • LRG_216p1:p.Lys57Thr
  • NC_000003.11:g.37038163A>C
  • NM_000249.3:c.170A>C
  • NM_001167618.1:c.-554A>C
  • p.K57T
Protein change:
K57T
Links:
dbSNP: rs587779955
NCBI 1000 Genomes Browser:
rs587779955
Molecular consequence:
  • NM_001167617.3:c.-120A>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001167618.3:c.-554A>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001167619.3:c.-462A>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001258274.3:c.-699A>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001354615.2:c.-457A>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001354616.2:c.-462A>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001354617.2:c.-554A>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001354618.2:c.-554A>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001354619.2:c.-554A>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001354620.2:c.-120A>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001354621.2:c.-647A>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001354622.2:c.-760A>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001354624.2:c.-657A>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001354625.2:c.-560A>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001354626.2:c.-657A>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001354627.2:c.-657A>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001258273.2:c.-517+3009A>C - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001354623.2:c.-723+2782A>C - intron variant - [Sequence Ontology: SO:0001627]
  • NM_000249.4:c.170A>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001258271.2:c.170A>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354628.2:c.170A>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354629.2:c.170A>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354630.2:c.170A>C - missense variant - [Sequence Ontology: SO:0001583]
Observations:
2

Condition(s)

Name:
Lynch syndrome
Identifiers:
MONDO: MONDO:0005835; MedGen: C4552100

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV004835243All of Us Research Program, National Institutes of Health
criteria provided, single submitter

(ACMG Guidelines, 2015)
Uncertain Significance
(Aug 14, 2023)
germlineclinical testing

PubMed (2)
[See all records that cite these PMIDs]

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknown2not providednot provided108544not providedclinical testing

Citations

PubMed

Frequency of mutations in individuals with breast cancer referred for BRCA1 and BRCA2 testing using next-generation sequencing with a 25-gene panel.

Tung N, Battelli C, Allen B, Kaldate R, Bhatnagar S, Bowles K, Timms K, Garber JE, Herold C, Ellisen L, Krejdovsky J, DeLeonardis K, Sedgwick K, Soltis K, Roa B, Wenstrup RJ, Hartman AR.

Cancer. 2015 Jan 1;121(1):25-33. doi: 10.1002/cncr.29010. Epub 2014 Sep 3.

PubMed [citation]
PMID:
25186627

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]
PMID:
25741868
PMCID:
PMC4544753

Details of each submission

From All of Us Research Program, National Institutes of Health, SCV004835243.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided2not providednot providedclinical testing PubMed (2)

Description

This missense variant replaces lysine with threonine at codon 57 of the MLH1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with breast cancer (PMID: 25186627). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknown108544not providednot provided2not providednot providednot provided

Last Updated: Sep 29, 2024