NM_000249.4(MLH1):c.143A>C (p.Gln48Pro) AND Hereditary nonpolyposis colorectal neoplasms

Clinical significance:Pathogenic (Last evaluated: Dec 19, 2019)

Review status:1 star out of maximum of 4 stars

criteria provided, single submitter

Based on:
1 submission [Details]
Record status:
current
Accession:
RCV001069994.2

Allele description [Variation Report for NM_000249.4(MLH1):c.143A>C (p.Gln48Pro)]

NM_000249.4(MLH1):c.143A>C (p.Gln48Pro)

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.143A>C (p.Gln48Pro)
HGVS:
  • NC_000003.12:g.36996645A>C
  • NG_007109.2:g.8296A>C
  • NG_008418.1:g.1660T>G
  • NM_000249.3:c.143A>C
  • NM_000249.4:c.143A>CMANE SELECT
  • NM_001167617.3:c.-147A>C
  • NM_001167618.3:c.-581A>C
  • NM_001167619.3:c.-489A>C
  • NM_001258271.2:c.143A>C
  • NM_001258273.2:c.-517+2982A>C
  • NM_001258274.3:c.-726A>C
  • NM_001354615.2:c.-484A>C
  • NM_001354616.2:c.-489A>C
  • NM_001354617.2:c.-581A>C
  • NM_001354618.2:c.-581A>C
  • NM_001354619.2:c.-581A>C
  • NM_001354620.2:c.-147A>C
  • NM_001354621.2:c.-674A>C
  • NM_001354622.2:c.-787A>C
  • NM_001354623.2:c.-723+2755A>C
  • NM_001354624.2:c.-684A>C
  • NM_001354625.2:c.-587A>C
  • NM_001354626.2:c.-684A>C
  • NM_001354627.2:c.-684A>C
  • NM_001354628.2:c.143A>C
  • NM_001354629.2:c.143A>C
  • NM_001354630.2:c.143A>C
  • NP_000240.1:p.Gln48Pro
  • NP_000240.1:p.Gln48Pro
  • NP_001245200.1:p.Gln48Pro
  • NP_001341557.1:p.Gln48Pro
  • NP_001341558.1:p.Gln48Pro
  • NP_001341559.1:p.Gln48Pro
  • LRG_216t1:c.143A>C
  • LRG_216:g.8296A>C
  • LRG_216p1:p.Gln48Pro
  • NC_000003.11:g.37038136A>C
Protein change:
Q48P
Links:
dbSNP: rs587778914
NCBI 1000 Genomes Browser:
rs587778914
Molecular consequence:
  • NM_001167617.3:c.-147A>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001167618.3:c.-581A>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001167619.3:c.-489A>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001258274.3:c.-726A>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001354615.2:c.-484A>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001354616.2:c.-489A>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001354617.2:c.-581A>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001354618.2:c.-581A>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001354619.2:c.-581A>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001354620.2:c.-147A>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001354621.2:c.-674A>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001354622.2:c.-787A>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001354624.2:c.-684A>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001354625.2:c.-587A>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001354626.2:c.-684A>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001354627.2:c.-684A>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
  • NM_001258273.2:c.-517+2982A>C - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001354623.2:c.-723+2755A>C - intron variant - [Sequence Ontology: SO:0001627]
  • NM_000249.3:c.143A>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_000249.4:c.143A>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001258271.2:c.143A>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354628.2:c.143A>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354629.2:c.143A>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354630.2:c.143A>C - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Hereditary nonpolyposis colorectal neoplasms
Identifiers:
MedGen: C0009405; Orphanet: 443090

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV001235200Invitaecriteria provided, single submitter
Pathogenic
(Dec 19, 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

Citations

PubMed

Q48P mutation in the hMLH1 gene associated with Lynch syndrome in three Hungarian families.

Tanyi M, Olasz J, Tanyi JL, Tóth L, Antal-Szalmás P, Bubán T, András C, Urbancsek H, Garami Z, Csuka O, Damjanovich L.

Fam Cancer. 2012 Sep;11(3):519-24. doi: 10.1007/s10689-012-9515-9.

PubMed [citation]
PMID:
22395473

Missense variants in hMLH1 identified in patients from the German HNPCC consortium and functional studies.

Hardt K, Heick SB, Betz B, Goecke T, Yazdanparast H, Küppers R, Servan K, Steinke V, Rahner N, Morak M, Holinski-Feder E, Engel C, Möslein G, Schackert HK, von Knebel Doeberitz M, Pox C; Peter Propping.; German HNPCC consortium., Hegemann JH, Royer-Pokora B.

Fam Cancer. 2011 Jun;10(2):273-84. doi: 10.1007/s10689-011-9431-4.

PubMed [citation]
PMID:
21404117
See all PubMed Citations (3)

Details of each submission

From Invitae, SCV001235200.2

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

Description

This sequence change replaces glutamine with proline at codon 48 of the MLH1 protein (p.Gln48Pro). The glutamine residue is highly conserved and there is a moderate physicochemical difference between glutamine and proline. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with Lynch syndrome (PMID: 22395473, 21404117). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 89739). This variant has been reported to affect MLH1 protein function (PMID: 21404117). For these reasons, this variant has been classified as Pathogenic.

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

Last Updated: Oct 30, 2021

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