NM_000249.4(MLH1):c.187G>C (p.Asp63His) AND Hereditary nonpolyposis colorectal neoplasms

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Jul 11, 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:: RCV001230871.4

Allele description [Variation Report for NM_000249.4(MLH1):c.187G>C (p.Asp63His)]

NM_000249.4(MLH1):c.187G>C (p.Asp63His)

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.187G>C (p.Asp63His)

HGVS:

NC_000003.12:g.36996689G>C
NG_007109.2:g.8340G>C
NG_008418.1:g.1616C>G
NM_000249.4:c.187G>CMANE SELECT
NM_001167617.3:c.-103G>C
NM_001167618.3:c.-537G>C
NM_001167619.3:c.-445G>C
NM_001258271.2:c.187G>C
NM_001258273.2:c.-517+3026G>C
NM_001258274.3:c.-682G>C
NM_001354615.2:c.-440G>C
NM_001354616.2:c.-445G>C
NM_001354617.2:c.-537G>C
NM_001354618.2:c.-537G>C
NM_001354619.2:c.-537G>C
NM_001354620.2:c.-103G>C
NM_001354621.2:c.-630G>C
NM_001354622.2:c.-743G>C
NM_001354623.2:c.-723+2799G>C
NM_001354624.2:c.-640G>C
NM_001354625.2:c.-543G>C
NM_001354626.2:c.-640G>C
NM_001354627.2:c.-640G>C
NM_001354628.2:c.187G>C
NM_001354629.2:c.187G>C
NM_001354630.2:c.187G>C
NP_000240.1:p.Asp63His
NP_001245200.1:p.Asp63His
NP_001341557.1:p.Asp63His
NP_001341558.1:p.Asp63His
NP_001341559.1:p.Asp63His
LRG_216t1:c.187G>C
LRG_216:g.8340G>C
NC_000003.11:g.37038180G>C
NM_000249.3:c.187G>C

Protein change:

D63H

Links:

dbSNP: rs63750850

NCBI 1000 Genomes Browser:

rs63750850

Molecular consequence:

NM_001167617.3:c.-103G>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001167618.3:c.-537G>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001167619.3:c.-445G>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001258274.3:c.-682G>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354615.2:c.-440G>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354616.2:c.-445G>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354617.2:c.-537G>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354618.2:c.-537G>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354619.2:c.-537G>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354620.2:c.-103G>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354621.2:c.-630G>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354622.2:c.-743G>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354624.2:c.-640G>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354625.2:c.-543G>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354626.2:c.-640G>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354627.2:c.-640G>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001258273.2:c.-517+3026G>C - intron variant - [Sequence Ontology: SO:0001627]
NM_001354623.2:c.-723+2799G>C - intron variant - [Sequence Ontology: SO:0001627]
NM_000249.4:c.187G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001258271.2:c.187G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354628.2:c.187G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354629.2:c.187G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354630.2:c.187G>C - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

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

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001403371	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Jul 11, 2022)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 16083711, 17569143, 17594722, 21120944, 26895986, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001403371

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Jul 11, 2022)

germline

clinical testing

PubMed (6)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Functional significance and clinical phenotype of nontruncating mismatch repair variants of MLH1.

Raevaara TE, Korhonen MK, Lohi H, Hampel H, Lynch E, Lönnqvist KE, Holinski-Feder E, Sutter C, McKinnon W, Duraisamy S, Gerdes AM, Peltomäki P, Kohonen-Ccorish M, Mangold E, Macrae F, Greenblatt M, de la Chapelle A, Nyström M.

Gastroenterology. 2005 Aug;129(2):537-49.

PubMed [citation]

PMID:: 16083711

Germline MLH1 and MSH2 mutational spectrum including frequent large genomic aberrations in Hungarian hereditary non-polyposis colorectal cancer families: implications for genetic testing.

Papp J, Kovacs ME, Olah E.

World J Gastroenterol. 2007 May 21;13(19):2727-32.

PubMed [citation]

PMID:: 17569143
PMCID:: PMC4147123

See all PubMed Citations (6)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001403371.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Asp63 amino acid residue in MLH1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16083711, 17569143, 17594722, 21120944). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt MLH1 protein function. ClinVar contains an entry for this variant (Variation ID: 957817). This missense change has been observed in individual(s) with clinical features of Lynch syndrome (PMID: 26895986). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces aspartic acid, which is acidic and polar, with histidine, which is basic and polar, at codon 63 of the MLH1 protein (p.Asp63His).

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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