U.S. flag

An official website of the United States government

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

Germline classification:
Likely benign (3 submissions)
Last evaluated:
Apr 18, 2024
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:
RCV000216577.14

Allele description [Variation Report for NM_000249.4(MLH1):c.974G>A (p.Arg325Gln)]

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

Recent activity

Clear Turn Off Turn On

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...

Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV000279335GeneDx
criteria provided, single submitter

(GeneDx Variant Classification (06012015))		Likely benign
(Oct 11, 2017) 		germlineclinical testing

Citation Link,

SCV000595808Genetic Services Laboratory, University of Chicago
criteria provided, single submitter

(ACMG Guidelines, 2015)		Likely benign
(Apr 12, 2017) 		germlineclinical testing

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

SCV000917656Women's Health and Genetics/Laboratory Corporation of America, LabCorp
criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)		Likely benign
(Apr 18, 2024) 		germlineclinical testing

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

Citation Link

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineyesnot providednot providednot providednot providednot providedclinical testing
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing
not providedgermlinenonot providednot providednot providednot providednot providedclinical 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

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot 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.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providednot providednot providednot providednot providednot provided

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

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlinenonot providednot providednot providednot providednot providednot providednot provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000917656.4

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical 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 estimated 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). These results showed no damaging effect of this variant. The following publications have been ascertained in the context of this evaluation (PMID: 22736432, 24953332, 28591715, 30306255, 31391288, 31784484). ClinVar contains an entry for this variant (Variation ID: 90456). Based on the evidence outlined above, the variant was classified as likely benign.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Oct 13, 2024