NM_000249.4(MLH1):c.1040C>A (p.Thr347Asn) AND not specified

Germline classification:: Conflicting interpretations of pathogenicity (7 submissions)
Last evaluated:: Aug 15, 2023
Review status:: criteria provided, conflicting classifications

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:: RCV000212529.22

Allele description [Variation Report for NM_000249.4(MLH1):c.1040C>A (p.Thr347Asn)]

NM_000249.4(MLH1):c.1040C>A (p.Thr347Asn)

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.1040C>A (p.Thr347Asn)

Other names:

p.T347N:ACT>AAT

HGVS:

NC_000003.12:g.37025638C>A
NG_007109.2:g.37289C>A
NM_000249.4:c.1040C>AMANE SELECT
NM_001167617.3:c.746C>A
NM_001167618.3:c.317C>A
NM_001167619.3:c.317C>A
NM_001258271.2:c.1040C>A
NM_001258273.2:c.317C>A
NM_001258274.3:c.317C>A
NM_001354615.2:c.317C>A
NM_001354616.2:c.317C>A
NM_001354617.2:c.317C>A
NM_001354618.2:c.317C>A
NM_001354619.2:c.317C>A
NM_001354620.2:c.746C>A
NM_001354621.2:c.17C>A
NM_001354622.2:c.17C>A
NM_001354623.2:c.17C>A
NM_001354624.2:c.-35C>A
NM_001354625.2:c.-35C>A
NM_001354626.2:c.-35C>A
NM_001354627.2:c.-35C>A
NM_001354628.2:c.1040C>A
NM_001354629.2:c.941C>A
NM_001354630.2:c.1040C>A
NP_000240.1:p.Thr347Asn
NP_000240.1:p.Thr347Asn
NP_001161089.1:p.Thr249Asn
NP_001161090.1:p.Thr106Asn
NP_001161091.1:p.Thr106Asn
NP_001245200.1:p.Thr347Asn
NP_001245202.1:p.Thr106Asn
NP_001245203.1:p.Thr106Asn
NP_001341544.1:p.Thr106Asn
NP_001341545.1:p.Thr106Asn
NP_001341546.1:p.Thr106Asn
NP_001341547.1:p.Thr106Asn
NP_001341548.1:p.Thr106Asn
NP_001341549.1:p.Thr249Asn
NP_001341550.1:p.Thr6Asn
NP_001341551.1:p.Thr6Asn
NP_001341552.1:p.Thr6Asn
NP_001341557.1:p.Thr347Asn
NP_001341558.1:p.Thr314Asn
NP_001341559.1:p.Thr347Asn
LRG_216t1:c.1040C>A
LRG_216:g.37289C>A
LRG_216p1:p.Thr347Asn
NC_000003.11:g.37067129C>A
NM_000249.3:c.1040C>A
p.T347N

Protein change:

T106N

Links:

dbSNP: rs201541505

NCBI 1000 Genomes Browser:

rs201541505

Molecular consequence:

NM_001354624.2:c.-35C>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354625.2:c.-35C>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354626.2:c.-35C>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354627.2:c.-35C>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_000249.4:c.1040C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001167617.3:c.746C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001167618.3:c.317C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001167619.3:c.317C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001258271.2:c.1040C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001258273.2:c.317C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001258274.3:c.317C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354615.2:c.317C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354616.2:c.317C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354617.2:c.317C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354618.2:c.317C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354619.2:c.317C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354620.2:c.746C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354621.2:c.17C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354622.2:c.17C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354623.2:c.17C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354628.2:c.1040C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354629.2:c.941C>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354630.2:c.1040C>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:: AllHighlyPenetrant
Identifiers:: MedGen: CN169374

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000539652	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	criteria provided, single submitter (LMM Criteria)	Uncertain significance (Dec 14, 2016)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000696093	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Likely benign (Apr 18, 2019)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 22949379, 27435373 Citation Link,
SCV001742303	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen - VKGL Data-share Consensus	no assertion criteria provided	Benign	germline	clinical testing
SCV001797959	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) - VKGL Data-share Consensus	no assertion criteria provided	Benign	germline	clinical testing
SCV001956507	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ - VKGL Data-share Consensus See additional submitters Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	no assertion criteria provided	Benign	germline	clinical testing
SCV002034317	Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute - VKGL Data-share Consensus See additional submitters Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	no assertion criteria provided	Benign	germline	clinical testing
SCV002552489	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely benign (Aug 15, 2023)	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	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

A systematic approach to assessing the clinical significance of genetic variants.

Duzkale H, Shen J, McLaughlin H, Alfares A, Kelly MA, Pugh TJ, Funke BH, Rehm HL, Lebo MS.

Clin Genet. 2013 Nov;84(5):453-63. doi: 10.1111/cge.12257.

PubMed [citation]

PMID:: 24033266
PMCID:: PMC3995020

A multifactorial likelihood model for MMR gene variant classification incorporating probabilities based on sequence bioinformatics and tumor characteristics: a report from the Colon Cancer Family Registry.

Thompson BA, Goldgar DE, Paterson C, Clendenning M, Walters R, Arnold S, Parsons MT, Michael D W, Gallinger S, Haile RW, Hopper JL, Jenkins MA, Lemarchand L, Lindor NM, Newcomb PA, Thibodeau SN; Colon Cancer Family Registry., Young JP, Buchanan DD, Tavtigian SV, Spurdle AB.

Hum Mutat. 2013 Jan;34(1):200-9. doi: 10.1002/humu.22213. Epub 2012 Oct 11.

PubMed [citation]

PMID:: 22949379
PMCID:: PMC3538359

See all PubMed Citations (4)

Details of each submission

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV000539652.1

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

Description

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: This variant is in the second base of exon 12 (of 19 exons). This variant is present in ExAC and gnomAD at a MaxMAF of 0.01% (15 alleles). It is classified in ClinVar as Benign by Ambry and an expert panel (InSiGHT - 3 stars) and as VUS by Invitae and GeneDx. It has not been reported in affected individuals but was seen in the Invitae database in a patient who had another PMS2 variant that was likely to explain disease.

#	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

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000696093.3

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

Description

Variant summary: MLH1 c.1040C>A (p.Thr347Asn) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 7.3e-05 in 206178 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in MLH1 causing Lynch Syndrome (7.3e-05 vs 0.00071), allowing no conclusion about variant significance. c.1040C>A has been reported in the literature in at-least one proband affected with colorectal cancer (Thompson_2013). This report(s) does not provide unequivocal conclusions about association of the variant with Lynch Syndrome. Additionally, it was reported in a patient with sporadic etiology for colorectal cancer as evidenced by BRAF mutation positivity, high MSI, and a negative MLH1 and PMS2 staining by IHC (van der Klift_2016). BRAF mutation and MLH1 promoter hypermethylation have been reported as strong predictors of a negative germline MMR mutational status (Parsons_2012, PMID 22368298). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as uncertain significance. Additionally, one submission indicates the variant co-occurred with a pathogenic PMS2 variant (variant not indicated). In addition, an expert panel submitter, InSiGHT, and another submitter (evaluation before 2014) have classified the variant as benign. Therefore, based on the evidence outlined above, the variant was classified as likely benign.

#	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

From Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen - VKGL Data-share Consensus, SCV001742303.3

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

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

From Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) - VKGL Data-share Consensus, SCV001797959.1

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

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

From Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ - VKGL Data-share Consensus, SCV001956507.1

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

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

From Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute - VKGL Data-share Consensus, SCV002034317.1

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

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

From Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital, SCV002552489.4

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

#	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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