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NM_000249.4(MLH1):c.2103G>C (p.Gln701His) AND Hereditary nonpolyposis colorectal neoplasms

Germline classification:
Pathogenic (1 submission)
Last evaluated:
Nov 1, 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:
RCV000694604.5

Allele description [Variation Report for NM_000249.4(MLH1):c.2103G>C (p.Gln701His)]

NM_000249.4(MLH1):c.2103G>C (p.Gln701His)

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.2103G>C (p.Gln701His)
HGVS:
  • NC_000003.12:g.37049017G>C
  • NG_007109.2:g.60668G>C
  • NM_000249.4:c.2103G>CMANE SELECT
  • NM_001167617.3:c.1809G>C
  • NM_001167618.3:c.1380G>C
  • NM_001167619.3:c.1380G>C
  • NM_001258271.2:c.1896+1334G>C
  • NM_001258273.2:c.1380G>C
  • NM_001258274.3:c.1380G>C
  • NM_001354615.2:c.1380G>C
  • NM_001354616.2:c.1380G>C
  • NM_001354617.2:c.1380G>C
  • NM_001354618.2:c.1380G>C
  • NM_001354619.2:c.1380G>C
  • NM_001354620.2:c.1809G>C
  • NM_001354621.2:c.1080G>C
  • NM_001354622.2:c.1080G>C
  • NM_001354623.2:c.1080G>C
  • NM_001354624.2:c.1029G>C
  • NM_001354625.2:c.1029G>C
  • NM_001354626.2:c.1029G>C
  • NM_001354627.2:c.1029G>C
  • NM_001354628.2:c.2010G>C
  • NM_001354629.2:c.2004G>C
  • NM_001354630.2:c.1938G>C
  • NP_000240.1:p.Gln701His
  • NP_000240.1:p.Gln701His
  • NP_001161089.1:p.Gln603His
  • NP_001161090.1:p.Gln460His
  • NP_001161091.1:p.Gln460His
  • NP_001245202.1:p.Gln460His
  • NP_001245203.1:p.Gln460His
  • NP_001341544.1:p.Gln460His
  • NP_001341545.1:p.Gln460His
  • NP_001341546.1:p.Gln460His
  • NP_001341547.1:p.Gln460His
  • NP_001341548.1:p.Gln460His
  • NP_001341549.1:p.Gln603His
  • NP_001341550.1:p.Gln360His
  • NP_001341551.1:p.Gln360His
  • NP_001341552.1:p.Gln360His
  • NP_001341553.1:p.Gln343His
  • NP_001341554.1:p.Gln343His
  • NP_001341555.1:p.Gln343His
  • NP_001341556.1:p.Gln343His
  • NP_001341557.1:p.Gln670His
  • NP_001341558.1:p.Gln668His
  • NP_001341559.1:p.Gln646His
  • LRG_216t1:c.2103G>C
  • LRG_216:g.60668G>C
  • LRG_216p1:p.Gln701His
  • NC_000003.11:g.37090508G>C
  • NM_000249.3:c.2103G>C
Protein change:
Q343H
Links:
dbSNP: rs63750603
NCBI 1000 Genomes Browser:
rs63750603
Molecular consequence:
  • NM_001258271.2:c.1896+1334G>C - intron variant - [Sequence Ontology: SO:0001627]
  • NM_000249.4:c.2103G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001167617.3:c.1809G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001167618.3:c.1380G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001167619.3:c.1380G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001258273.2:c.1380G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001258274.3:c.1380G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354615.2:c.1380G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354616.2:c.1380G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354617.2:c.1380G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354618.2:c.1380G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354619.2:c.1380G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354620.2:c.1809G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354621.2:c.1080G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354622.2:c.1080G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354623.2:c.1080G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354624.2:c.1029G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354625.2:c.1029G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354626.2:c.1029G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354627.2:c.1029G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354628.2:c.2010G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354629.2:c.2004G>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001354630.2:c.1938G>C - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Hereditary nonpolyposis colorectal neoplasms
Identifiers:
MeSH: D003123; MedGen: C0009405

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV000823055Labcorp Genetics (formerly Invitae), Labcorp
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))		Pathogenic
(Nov 1, 2023) 		germlineclinical testing

PubMed (8)
[See all records that cite these PMIDs]

Help

Summary from all submissions

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

Citations

PubMed

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

Universal screening for Lynch syndrome in a large consecutive cohort of Chinese colorectal cancer patients: High prevalence and unique molecular features.

Jiang W, Cai MY, Li SY, Bei JX, Wang F, Hampel H, Ling YH, Frayling IM, Sinicrope FA, Rodriguez-Bigas MA, Dignam JJ, Kerr DJ, Rosell R, Mao M, Li JB, Guo YM, Wu XY, Kong LH, Tang JH, Wu XD, Li CF, Chen JR, et al.

Int J Cancer. 2019 May 1;144(9):2161-2168. doi: 10.1002/ijc.32044. Epub 2019 Jan 9.

PubMed [citation]
PMID:
30521064
See all PubMed Citations (8)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000823055.3

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (8)

Description

This sequence change replaces glutamine, which is neutral and polar, with histidine, which is basic and polar, at codon 701 of the MLH1 protein (p.Gln701His). RNA analysis indicates that this missense change induces altered splicing and likely results in a shortened protein product. This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of Lynch syndrome (PMID: 15849733, 16341550, 21404117, 30521064, 31491536; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 90049). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this missense change results in skipping of exon 18, but is expected to preserve the integrity of the reading-frame (PMID: 15849733, 16341550). 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: Sep 29, 2024