NM_000249.4(MLH1):c.974G>A (p.Arg325Gln) AND not specified

This record was updated by the submitter. Please see the current version.

Germline classification:: Conflicting interpretations of pathogenicity (3 submissions)
Last evaluated:: Feb 21, 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:: RCV000216577.13

Allele description

NM_000249.4(MLH1):c.974G>A (p.Arg325Gln)

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.974G>A (p.Arg325Gln)

HGVS:

NC_000003.12:g.37020399G>A
NG_007109.2:g.32050G>A
NM_000249.4:c.974G>AMANE SELECT
NM_001167617.3:c.680G>A
NM_001167618.3:c.251G>A
NM_001167619.3:c.251G>A
NM_001258271.2:c.974G>A
NM_001258273.2:c.251G>A
NM_001258274.3:c.251G>A
NM_001354615.2:c.251G>A
NM_001354616.2:c.251G>A
NM_001354617.2:c.251G>A
NM_001354618.2:c.251G>A
NM_001354619.2:c.251G>A
NM_001354620.2:c.680G>A
NM_001354621.2:c.-50G>A
NM_001354622.2:c.-50G>A
NM_001354623.2:c.-50G>A
NM_001354624.2:c.-36-5238G>A
NM_001354625.2:c.-36-5238G>A
NM_001354626.2:c.-36-5238G>A
NM_001354627.2:c.-36-5238G>A
NM_001354628.2:c.974G>A
NM_001354629.2:c.875G>A
NM_001354630.2:c.974G>A
NP_000240.1:p.Arg325Gln
NP_000240.1:p.Arg325Gln
NP_001161089.1:p.Arg227Gln
NP_001161090.1:p.Arg84Gln
NP_001161091.1:p.Arg84Gln
NP_001245200.1:p.Arg325Gln
NP_001245202.1:p.Arg84Gln
NP_001245203.1:p.Arg84Gln
NP_001341544.1:p.Arg84Gln
NP_001341545.1:p.Arg84Gln
NP_001341546.1:p.Arg84Gln
NP_001341547.1:p.Arg84Gln
NP_001341548.1:p.Arg84Gln
NP_001341549.1:p.Arg227Gln
NP_001341557.1:p.Arg325Gln
NP_001341558.1:p.Arg292Gln
NP_001341559.1:p.Arg325Gln
LRG_216t1:c.974G>A
LRG_216:g.32050G>A
LRG_216p1:p.Arg325Gln
NC_000003.11:g.37061890G>A
NM_000249.3:c.974G>A
P40692:p.Arg325Gln
p.R325Q

Protein change:

R227Q

Links:

UniProtKB: P40692#VAR_012917; dbSNP: rs63750268

NCBI 1000 Genomes Browser:

rs63750268

Molecular consequence:

NM_001354621.2:c.-50G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354622.2:c.-50G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354623.2:c.-50G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001354624.2:c.-36-5238G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_001354625.2:c.-36-5238G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_001354626.2:c.-36-5238G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_001354627.2:c.-36-5238G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_000249.4:c.974G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001167617.3:c.680G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001167618.3:c.251G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001167619.3:c.251G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001258271.2:c.974G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001258273.2:c.251G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001258274.3:c.251G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354615.2:c.251G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354616.2:c.251G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354617.2:c.251G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354618.2:c.251G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354619.2:c.251G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354620.2:c.680G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354628.2:c.974G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354629.2:c.875G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354630.2:c.974G>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
SCV000279335	GeneDx	criteria provided, single submitter (GeneDx Variant Classification (06012015))	Likely benign (Oct 11, 2017)	germline	clinical testing	Citation Link,
SCV000595808	Genetic Services Laboratory, University of Chicago	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely benign (Apr 12, 2017)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000917656	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Uncertain significance (Feb 21, 2023)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 22736432, 24953332, 28591715, 30306255, 31391288, 31784484 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000279335

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification (06012015))

Likely benign
(Oct 11, 2017)

germline

clinical testing

Citation Link,

SCV000595808

Genetic Services Laboratory, University of Chicago

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely benign
(Apr 12, 2017)

germline

clinical testing

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

SCV000917656

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

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Uncertain significance
(Feb 21, 2023)

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	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	no	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

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

Comprehensive functional assessment of MLH1 variants of unknown significance.

Borràs E, Pineda M, Brieger A, Hinrichsen I, Gómez C, Navarro M, Balmaña J, Ramón y Cajal T, Torres A, Brunet J, Blanco I, Plotz G, Lázaro C, Capellá G.

Hum Mutat. 2012 Nov;33(11):1576-88. doi: 10.1002/humu.22142. Epub 2012 Jul 12. Erratum in: Hum Mutat. 2013 Jan;34(1):274.

PubMed [citation]

PMID:: 22736432

See all PubMed Citations (7)

Details of each submission

From GeneDx, SCV000279335.8

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

Description

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

#	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 Genetic Services Laboratory, University of Chicago, SCV000595808.1

#	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	no	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, SCV000917656.3

#	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.974G>A (p.Arg325Gln) results in a conservative amino acid change located in the DNA mismatch repair protein, S5 domain 2-like of the encoded protein sequence. Four 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 251356 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in MLH1 causing Hereditary Nonpolyposis Colorectal Cancer (4.4e-05 vs 0.00071), allowing no conclusion about variant significance. c.974G>A has been reported in the literature in individuals affected with Lynch Syndrome, including two families in which the variant appears to segregate with disease (two affected patients per family carrying the variant; Borras_2012, Castillejo_2014). Additionally, the variant was reported in MSI-high cancers, without strong evidence for causality (Deihimi_2017, Li_2020). These reports do not provide unequivocal conclusions about association of the variant with Lynch Syndrome. Suggesting a benign impact, functional studies including splicing assay, MMR assay, MLH1 expression and PMS2 expression, and MLH1 and PMS2 subcellular localization show the variant to have function similar to WT (Borras_2012). Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as likely benign. Based on the evidence outlined above, the variant was classified as a VUS - possibly benign variant.

#	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: May 19, 2024

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