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

Recent activity

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syt17 synaptotagmin 17 [Xenopus tropicalis]
syt17 synaptotagmin 17 [Xenopus tropicalis]
Gene ID:100125097

Gene
100125097[uid] AND (alive[prop]) (1)
Gene
glycerol-3-phosphate dehydrogenase [NAD(+)], cytoplasmic isoform 1 [Homo sapiens...
glycerol-3-phosphate dehydrogenase [NAD(+)], cytoplasmic isoform 1 [Homo sapiens]
gi|33695088|ref|NP_005267.2|

Protein
metalloproteinase inhibitor 1 isoform a precursor [Mus musculus]
metalloproteinase inhibitor 1 isoform a precursor [Mus musculus]
gi|113205065|ref|NP_035723.2|

Protein
Mus musculus RIKEN cDNA 4933427D14 gene (4933427D14Rik), transcript variant 1, m...
Mus musculus RIKEN cDNA 4933427D14 gene (4933427D14Rik), transcript variant 1, mRNA
gi|1371976213|ref|NM_028963.3|

Nucleotide

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000488009	Counsyl	criteria provided, single submitter (Counsyl Autosomal Dominant Disease Classification criteria (2015))	Likely benign (Dec 11, 2015)	unknown	clinical testing	PubMed (2) [See all records that cite these PMIDs] 22949387, 22736432 Counsyl Autosomal Dominant Disease Classification criteria (2015), Citation Link,
SCV004018133	Myriad Genetics, Inc.	criteria provided, single submitter (Myriad Autosomal Dominant, Autosomal Recessive and X-Linked Classification Criteria (2023))	Likely benign (Mar 14, 2023)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000488009

Counsyl

criteria provided, single submitter

(Counsyl Autosomal Dominant Disease Classification criteria (2015))

Likely benign
(Dec 11, 2015)

unknown

clinical testing

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

Counsyl Autosomal Dominant Disease Classification criteria (2015),

Citation Link,

SCV004018133

Myriad Genetics, Inc.

criteria provided, single submitter

(Myriad Autosomal Dominant, Autosomal Recessive and X-Linked Classification Criteria (2023))

Likely benign
(Mar 14, 2023)

unknown

clinical testing

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

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical 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

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

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

From Myriad Genetics, Inc., SCV004018133.1

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

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

Last Updated: Jul 23, 2024

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