NM_000249.4(MLH1):c.439G>C (p.Gly147Arg) AND Hereditary nonpolyposis colorectal neoplasms

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Aug 15, 2020
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:: RCV001296249.4

Allele description [Variation Report for NM_000249.4(MLH1):c.439G>C (p.Gly147Arg)]

NM_000249.4(MLH1):c.439G>C (p.Gly147Arg)

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.439G>C (p.Gly147Arg)

HGVS:

NC_000003.12:g.37007049G>C
NG_007109.2:g.18700G>C
NM_000249.4:c.439G>CMANE SELECT
NM_001167617.3:c.145G>C
NM_001167618.3:c.-285G>C
NM_001167619.3:c.-193G>C
NM_001258271.2:c.439G>C
NM_001258273.2:c.-285G>C
NM_001258274.3:c.-285G>C
NM_001354615.2:c.-193G>C
NM_001354616.2:c.-193G>C
NM_001354617.2:c.-285G>C
NM_001354618.2:c.-285G>C
NM_001354619.2:c.-285G>C
NM_001354620.2:c.145G>C
NM_001354621.2:c.-378G>C
NM_001354622.2:c.-491G>C
NM_001354623.2:c.-491G>C
NM_001354624.2:c.-388G>C
NM_001354625.2:c.-296G>C
NM_001354626.2:c.-388G>C
NM_001354627.2:c.-388G>C
NM_001354628.2:c.439G>C
NM_001354629.2:c.340G>C
NM_001354630.2:c.439G>C
NP_000240.1:p.Gly147Arg
NP_000240.1:p.Gly147Arg
NP_001161089.1:p.Gly49Arg
NP_001245200.1:p.Gly147Arg
NP_001341549.1:p.Gly49Arg
NP_001341557.1:p.Gly147Arg
NP_001341558.1:p.Gly114Arg
NP_001341559.1:p.Gly147Arg
LRG_216t1:c.439G>C
LRG_216:g.18700G>C
LRG_216p1:p.Gly147Arg
NC_000003.11:g.37048540G>C
NM_000249.3:c.439G>C

Protein change:

G114R

Links:

dbSNP: rs267607747

NCBI 1000 Genomes Browser:

rs267607747

Molecular consequence:

NM_001167618.3:c.-285G>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001167619.3:c.-193G>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001258273.2:c.-285G>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001258274.3:c.-285G>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354615.2:c.-193G>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354616.2:c.-193G>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354617.2:c.-285G>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354618.2:c.-285G>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354619.2:c.-285G>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354621.2:c.-378G>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354622.2:c.-491G>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354623.2:c.-491G>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354624.2:c.-388G>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354625.2:c.-296G>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354626.2:c.-388G>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354627.2:c.-388G>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_000249.4:c.439G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001167617.3:c.145G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001258271.2:c.439G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354620.2:c.145G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354628.2:c.439G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354629.2:c.340G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354630.2:c.439G>C - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

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

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cytochrome oxidase subunit 1, partial (mitochondrion) [Hermania scabra]
cytochrome oxidase subunit 1, partial (mitochondrion) [Hermania scabra]
gi|459926690|gb|AGG84206.1|

Protein
cytochrome oxidase subunit 1, partial (mitochondrion) [Hermania indistincta]
cytochrome oxidase subunit 1, partial (mitochondrion) [Hermania indistincta]
gi|908309315|gb|AKT25680.1|

Protein

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001485207	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Aug 15, 2020)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 18566915, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001485207

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Aug 15, 2020)

germline

clinical testing

PubMed (2)
[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

Major contribution from recurrent alterations and MSH6 mutations in the Danish Lynch syndrome population.

Nilbert M, Wikman FP, Hansen TV, Krarup HB, Orntoft TF, Nielsen FC, Sunde L, Gerdes AM, Cruger D, Timshel S, Bisgaard ML, Bernstein I, Okkels H.

Fam Cancer. 2009;8(1):75-83. doi: 10.1007/s10689-008-9199-3. Epub 2008 Jun 20.

PubMed [citation]

PMID:: 18566915

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001485207.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

This sequence change replaces glycine with arginine at codon 147 of the MLH1 protein (p.Gly147Arg). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and arginine. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. 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. This variant has been observed in individual(s) with clinical features of Lynch syndrome (PMID: 18566915). This variant is not present in population databases (ExAC no frequency).

#	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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