NM_000249.4(MLH1):c.546G>C (p.Arg182Ser) AND Hereditary nonpolyposis colorectal neoplasms

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Feb 18, 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:: RCV001956890.4

Allele description [Variation Report for NM_000249.4(MLH1):c.546G>C (p.Arg182Ser)]

NM_000249.4(MLH1):c.546G>C (p.Arg182Ser)

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.546G>C (p.Arg182Ser)

HGVS:

NC_000003.12:g.37011820G>C
NG_007109.2:g.23471G>C
NM_000249.4:c.546G>CMANE SELECT
NM_001167617.3:c.252G>C
NM_001167618.3:c.-178G>C
NM_001167619.3:c.-178G>C
NM_001258271.2:c.546G>C
NM_001258273.2:c.-178G>C
NM_001258274.3:c.-178G>C
NM_001354615.2:c.-178G>C
NM_001354616.2:c.-178G>C
NM_001354617.2:c.-178G>C
NM_001354618.2:c.-178G>C
NM_001354619.2:c.-178G>C
NM_001354620.2:c.252G>C
NM_001354621.2:c.-271G>C
NM_001354622.2:c.-384G>C
NM_001354623.2:c.-384G>C
NM_001354624.2:c.-281G>C
NM_001354625.2:c.-281G>C
NM_001354626.2:c.-281G>C
NM_001354627.2:c.-281G>C
NM_001354628.2:c.546G>C
NM_001354629.2:c.447G>C
NM_001354630.2:c.546G>C
NP_000240.1:p.Arg182Ser
NP_001161089.1:p.Arg84Ser
NP_001245200.1:p.Arg182Ser
NP_001341549.1:p.Arg84Ser
NP_001341557.1:p.Arg182Ser
NP_001341558.1:p.Arg149Ser
NP_001341559.1:p.Arg182Ser
LRG_216:g.23471G>C
NC_000003.11:g.37053311G>C

Protein change:

R149S

Links:

dbSNP: rs2125805259

NCBI 1000 Genomes Browser:

rs2125805259

Molecular consequence:

NM_001167618.3:c.-178G>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001167619.3:c.-178G>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001258273.2:c.-178G>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001258274.3:c.-178G>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354615.2:c.-178G>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354616.2:c.-178G>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354617.2:c.-178G>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354618.2:c.-178G>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354619.2:c.-178G>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354621.2:c.-271G>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354622.2:c.-384G>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354623.2:c.-384G>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354624.2:c.-281G>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354625.2:c.-281G>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354626.2:c.-281G>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354627.2:c.-281G>C - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_000249.4:c.546G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001167617.3:c.252G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001258271.2:c.546G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354620.2:c.252G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354628.2:c.546G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354629.2:c.447G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001354630.2:c.546G>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
SCV002250074	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Feb 18, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002250074

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Feb 18, 2022)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

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

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, SCV002250074.3

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

Description

Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. This variant has not been reported in the literature in individuals affected with MLH1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with serine, which is neutral and polar, at codon 182 of the MLH1 protein (p.Arg182Ser).

#	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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