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NM_000249.4(MLH1):c.974G>A (p.Arg325Gln) AND Colorectal cancer, hereditary nonpolyposis, type 2

Germline classification:
Likely benign (2 submissions)
Last evaluated:
Mar 14, 2023
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:
RCV000409264.4

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)

Name:
Colorectal cancer, hereditary nonpolyposis, type 2 (LYNCH2)
Synonyms:
COLON CANCER, FAMILIAL NONPOLYPOSIS, TYPE 2; Lynch syndrome II; MLH1-Related Lynch Syndrome; See all synonyms [MedGen]
Identifiers:
MONDO: MONDO:0012249; MedGen: C1333991; Orphanet: 144; OMIM: 609310

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV000488009Counsyl
criteria provided, single submitter

(Counsyl Autosomal Dominant Disease Classification criteria (2015))		Likely benign
(Dec 11, 2015) 		unknownclinical testing

PubMed (2)
[See all records that cite these PMIDs]

Counsyl Autosomal Dominant Disease Classification criteria (2015),

Citation Link,

SCV004018133Myriad Genetics, Inc.
criteria provided, single submitter

(Myriad Autosomal Dominant, Autosomal Recessive and X-Linked Classification Criteria (2023))		Likely benign
(Mar 14, 2023) 		unknownclinical testing

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

Citation Link

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedunknownunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Calibration of multiple in silico tools for predicting pathogenicity of mismatch repair gene missense substitutions.

Thompson BA, Greenblatt MS, Vallee MP, Herkert JC, Tessereau C, Young EL, Adzhubey IA, Li B, Bell R, Feng B, Mooney SD, Radivojac P, Sunyaev SR, Frebourg T, Hofstra RM, Sijmons RH, Boucher K, Thomas A, Goldgar DE, Spurdle AB, Tavtigian SV.

Hum Mutat. 2013 Jan;34(1):255-65. doi: 10.1002/humu.22214. Epub 2012 Oct 22.

PubMed [citation]
PMID:
22949387
PMCID:
PMC4318556

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 (3)

Details of each submission

From Counsyl, SCV000488009.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (2)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1unknownunknownnot providednot providednot providednot providednot providednot providednot provided

From Myriad Genetics, Inc., SCV004018133.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)

Description

This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752].

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

Last Updated: Oct 13, 2024