NM_000249.4(MLH1):c.1460G>A (p.Arg487Gln) AND not specified

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Mar 4, 2025
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV004595908.3

Allele description [Variation Report for NM_000249.4(MLH1):c.1460G>A (p.Arg487Gln)]

NM_000249.4(MLH1):c.1460G>A (p.Arg487Gln)

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.1460G>A (p.Arg487Gln)

HGVS:

NC_000003.12:g.37028834G>A
NG_007109.2:g.40485G>A
NM_000249.4:c.1460G>AMANE SELECT
NM_001167617.3:c.1166G>A
NM_001167618.3:c.737G>A
NM_001167619.3:c.737G>A
NM_001258271.2:c.1460G>A
NM_001258273.2:c.737G>A
NM_001258274.3:c.737G>A
NM_001354615.2:c.737G>A
NM_001354616.2:c.737G>A
NM_001354617.2:c.737G>A
NM_001354618.2:c.737G>A
NM_001354619.2:c.737G>A
NM_001354620.2:c.1166G>A
NM_001354621.2:c.437G>A
NM_001354622.2:c.437G>A
NM_001354623.2:c.437G>A
NM_001354624.2:c.386G>A
NM_001354625.2:c.386G>A
NM_001354626.2:c.386G>A
NM_001354627.2:c.386G>A
NM_001354628.2:c.1460G>A
NM_001354629.2:c.1361G>A
NM_001354630.2:c.1460G>A
NP_000240.1:p.Arg487Gln
NP_000240.1:p.Arg487Gln
NP_001161089.1:p.Arg389Gln
NP_001161090.1:p.Arg246Gln
NP_001161091.1:p.Arg246Gln
NP_001245200.1:p.Arg487Gln
NP_001245202.1:p.Arg246Gln
NP_001245203.1:p.Arg246Gln
NP_001341544.1:p.Arg246Gln
NP_001341545.1:p.Arg246Gln
NP_001341546.1:p.Arg246Gln
NP_001341547.1:p.Arg246Gln
NP_001341548.1:p.Arg246Gln
NP_001341549.1:p.Arg389Gln
NP_001341550.1:p.Arg146Gln
NP_001341551.1:p.Arg146Gln
NP_001341552.1:p.Arg146Gln
NP_001341553.1:p.Arg129Gln
NP_001341554.1:p.Arg129Gln
NP_001341555.1:p.Arg129Gln
NP_001341556.1:p.Arg129Gln
NP_001341557.1:p.Arg487Gln
NP_001341558.1:p.Arg454Gln
NP_001341559.1:p.Arg487Gln
LRG_216t1:c.1460G>A
LRG_216:g.40485G>A
LRG_216p1:p.Arg487Gln
NC_000003.11:g.37070325G>A
NM_000249.3:c.1460G>A

Protein change:

R129Q

Links:

dbSNP: rs587778917

NCBI 1000 Genomes Browser:

rs587778917

Molecular consequence:

NM_000249.4:c.1460G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001167617.3:c.1166G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001167618.3:c.737G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001167619.3:c.737G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001258271.2:c.1460G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001258273.2:c.737G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001258274.3:c.737G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354615.2:c.737G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354616.2:c.737G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354617.2:c.737G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354618.2:c.737G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354619.2:c.737G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354620.2:c.1166G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354621.2:c.437G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354622.2:c.437G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354623.2:c.437G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354624.2:c.386G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354625.2:c.386G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354626.2:c.386G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354627.2:c.386G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354628.2:c.1460G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354629.2:c.1361G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354630.2:c.1460G>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
SCV005090578	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Mar 4, 2025)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV005203525	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Uncertain significance (Jul 16, 2024)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 22290698, 25186627, 36356413, 34326862, 36531003, 33181636 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV005090578

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Mar 4, 2025)

germline

clinical testing

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

SCV005203525

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Uncertain significance
(Jul 16, 2024)

germline

clinical testing

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

Citation Link

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

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee.

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Classification of mismatch repair gene missense variants with PON-MMR.

Ali H, Olatubosun A, Vihinen M.

Hum Mutat. 2012 Apr;33(4):642-50. doi: 10.1002/humu.22038.

PubMed [citation]

PMID:: 22290698

See all PubMed Citations (7)

Details of each submission

From Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital, SCV005090578.2

#	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

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV005203525.1

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

Description

Variant summary: MLH1 c.1460G>A (p.Arg487Gln) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4.4e-05 in 251478 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in MLH1 causing Lynch Syndrome (4.4e-05 vs 0.00071), allowing no conclusion about variant significance. c.1460G>A has been reported in the literature in individuals affected with various types of cancer and/or individuals undergoing cancer testing (example: Andrikopoulou_2022, Bhai_2021, Fricke_2020, Poliani_2022, Tung_2015). These report(s) do not provide unequivocal conclusions about association of the variant with Lynch Syndrome. One publication predicts the variant to be neutral based on a consensus predictor (Ali_20112). The following publications have been ascertained in the context of this evaluation (PMID: 22290698, 36531003, 34326862, 33181636, 36356413, 25186627). ClinVar contains an entry for this variant (Variation ID: 89745). Based on the evidence outlined above, the variant was classified as 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: Mar 16, 2025

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