NM_000249.4(MLH1):c.409G>A (p.Ala137Thr) AND Hereditary nonpolyposis colorectal neoplasms

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Jan 30, 2024
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:: RCV001366628.4

Allele description [Variation Report for NM_000249.4(MLH1):c.409G>A (p.Ala137Thr)]

NM_000249.4(MLH1):c.409G>A (p.Ala137Thr)

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.409G>A (p.Ala137Thr)

HGVS:

NC_000003.12:g.37007019G>A
NG_007109.2:g.18670G>A
NM_000249.2:c.409G>A
NM_000249.4:c.409G>AMANE SELECT
NM_001167617.3:c.115G>A
NM_001167618.3:c.-315G>A
NM_001167619.3:c.-223G>A
NM_001258271.2:c.409G>A
NM_001258273.2:c.-315G>A
NM_001258274.3:c.-315G>A
NM_001354615.2:c.-223G>A
NM_001354616.2:c.-223G>A
NM_001354617.2:c.-315G>A
NM_001354618.2:c.-315G>A
NM_001354619.2:c.-315G>A
NM_001354620.2:c.115G>A
NM_001354621.2:c.-408G>A
NM_001354622.2:c.-521G>A
NM_001354623.2:c.-521G>A
NM_001354624.2:c.-418G>A
NM_001354625.2:c.-326G>A
NM_001354626.2:c.-418G>A
NM_001354627.2:c.-418G>A
NM_001354628.2:c.409G>A
NM_001354629.2:c.310G>A
NM_001354630.2:c.409G>A
NP_000240.1:p.Ala137Thr
NP_000240.1:p.Ala137Thr
NP_001161089.1:p.Ala39Thr
NP_001245200.1:p.Ala137Thr
NP_001341549.1:p.Ala39Thr
NP_001341557.1:p.Ala137Thr
NP_001341558.1:p.Ala104Thr
NP_001341559.1:p.Ala137Thr
LRG_216t1:c.409G>A
LRG_216:g.18670G>A
LRG_216p1:p.Ala137Thr
NC_000003.11:g.37048510G>A
NM_000249.3:c.409G>A

Protein change:

A104T

Links:

dbSNP: rs756888142

NCBI 1000 Genomes Browser:

rs756888142

Molecular consequence:

NM_001167618.3:c.-315G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001167619.3:c.-223G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001258273.2:c.-315G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001258274.3:c.-315G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354615.2:c.-223G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354616.2:c.-223G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354617.2:c.-315G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354618.2:c.-315G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354619.2:c.-315G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354621.2:c.-408G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354622.2:c.-521G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354623.2:c.-521G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354624.2:c.-418G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354625.2:c.-326G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354626.2:c.-418G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354627.2:c.-418G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_000249.4:c.409G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001167617.3:c.115G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001258271.2:c.409G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354620.2:c.115G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354628.2:c.409G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354629.2:c.310G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354630.2:c.409G>A - 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
SCV001562937	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Jan 30, 2024)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 27601186, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001562937

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Jan 30, 2024)

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

Mismatch repair gene mutation spectrum in the Swedish Lynch syndrome population.

Lagerstedt-Robinson K, Rohlin A, Aravidis C, Melin B, Nordling M, Stenmark-Askmalm M, Lindblom A, Nilbert M.

Oncol Rep. 2016 Nov;36(5):2823-2835. doi: 10.3892/or.2016.5060. Epub 2016 Sep 1.

PubMed [citation]

PMID:: 27601186

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, SCV001562937.3

#	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 alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 137 of the MLH1 protein (p.Ala137Thr). This variant is present in population databases (rs756888142, gnomAD 0.004%). This missense change has been observed in individual(s) with clinical features of Lynch syndrome (PMID: 27601186). ClinVar contains an entry for this variant (Variation ID: 234444). 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 not expected to disrupt MLH1 protein function with a negative predictive value of 95%. 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.

#	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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