NM_000249.4(MLH1):c.1166G>A (p.Arg389Gln) AND Colorectal cancer, hereditary nonpolyposis, type 2

Germline classification:: Conflicting interpretations of pathogenicity (5 submissions)
Last evaluated:: Oct 18, 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:: RCV000412195.11

Allele description [Variation Report for NM_000249.4(MLH1):c.1166G>A (p.Arg389Gln)]

NM_000249.4(MLH1):c.1166G>A (p.Arg389Gln)

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.1166G>A (p.Arg389Gln)

HGVS:

NC_000003.12:g.37025764G>A
NG_007109.2:g.37415G>A
NM_000249.4:c.1166G>AMANE SELECT
NM_001167617.3:c.872G>A
NM_001167618.3:c.443G>A
NM_001167619.3:c.443G>A
NM_001258271.2:c.1166G>A
NM_001258273.2:c.443G>A
NM_001258274.3:c.443G>A
NM_001354615.2:c.443G>A
NM_001354616.2:c.443G>A
NM_001354617.2:c.443G>A
NM_001354618.2:c.443G>A
NM_001354619.2:c.443G>A
NM_001354620.2:c.872G>A
NM_001354621.2:c.143G>A
NM_001354622.2:c.143G>A
NM_001354623.2:c.143G>A
NM_001354624.2:c.92G>A
NM_001354625.2:c.92G>A
NM_001354626.2:c.92G>A
NM_001354627.2:c.92G>A
NM_001354628.2:c.1166G>A
NM_001354629.2:c.1067G>A
NM_001354630.2:c.1166G>A
NP_000240.1:p.Arg389Gln
NP_000240.1:p.Arg389Gln
NP_001161089.1:p.Arg291Gln
NP_001161090.1:p.Arg148Gln
NP_001161091.1:p.Arg148Gln
NP_001245200.1:p.Arg389Gln
NP_001245202.1:p.Arg148Gln
NP_001245203.1:p.Arg148Gln
NP_001341544.1:p.Arg148Gln
NP_001341545.1:p.Arg148Gln
NP_001341546.1:p.Arg148Gln
NP_001341547.1:p.Arg148Gln
NP_001341548.1:p.Arg148Gln
NP_001341549.1:p.Arg291Gln
NP_001341550.1:p.Arg48Gln
NP_001341551.1:p.Arg48Gln
NP_001341552.1:p.Arg48Gln
NP_001341553.1:p.Arg31Gln
NP_001341554.1:p.Arg31Gln
NP_001341555.1:p.Arg31Gln
NP_001341556.1:p.Arg31Gln
NP_001341557.1:p.Arg389Gln
NP_001341558.1:p.Arg356Gln
NP_001341559.1:p.Arg389Gln
LRG_216t1:c.1166G>A
LRG_216:g.37415G>A
LRG_216p1:p.Arg389Gln
NC_000003.11:g.37067255G>A
NM_000249.3:c.1166G>A
p.R389Q

Protein change:

R148Q

Links:

dbSNP: rs63750361

NCBI 1000 Genomes Browser:

rs63750361

Molecular consequence:

NM_000249.4:c.1166G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001167617.3:c.872G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001167618.3:c.443G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001167619.3:c.443G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001258271.2:c.1166G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001258273.2:c.443G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001258274.3:c.443G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354615.2:c.443G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354616.2:c.443G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354617.2:c.443G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354618.2:c.443G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354619.2:c.443G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354620.2:c.872G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354621.2:c.143G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354622.2:c.143G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354623.2:c.143G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354624.2:c.92G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354625.2:c.92G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354626.2:c.92G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354627.2:c.92G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354628.2:c.1166G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354629.2:c.1067G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001354630.2:c.1166G>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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At.49114 AND (alive[prop]) (1)
Gene
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GDPD2 PLC-like phosphodiesterases superfamily protein [Arabidopsis thaliana]
Gene ID:834110

Gene
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gi|1133639402|emb|LT708304.1|

Nucleotide
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Gene
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gi|225403205|gnl|gcv|TCVSP-WEISS-00 b|FJ647219.1|

Nucleotide

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000488060	Counsyl	criteria provided, single submitter (Counsyl Autosomal Dominant Disease Classification criteria (2015))	Uncertain significance (Dec 18, 2015)	unknown	clinical testing	PubMed (3) [See all records that cite these PMIDs] 22703879, 23047549, 17510385 Counsyl Autosomal Dominant Disease Classification criteria (2015), Citation Link,
SCV001307795	Illumina Laboratory Services, Illumina	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019)	Uncertain significance (Jun 14, 2018)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 16995940, 17510385, 25579085, 22703879, 26817999, 24933000 Citation Link,
SCV001482845	Baylor Genetics - CSER-TexasKidsCanSeq	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Feb 11, 2020)	maternal	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004018165	Myriad Genetics, Inc.	criteria provided, single submitter (Myriad Autosomal Dominant, Autosomal Recessive and X-Linked Classification Criteria (2023))	Benign (Mar 15, 2023)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link,
SCV004171497	St. Jude Molecular Pathology, St. Jude Children's Research Hospital	criteria provided, single submitter (St. Jude Assertion Criteria 2020)	Uncertain significance (Oct 18, 2023)	germline	clinical testing	Citation Link

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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
not provided	maternal	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Frequency of mutations in mismatch repair genes in a population-based study of women with ovarian cancer.

Pal T, Akbari MR, Sun P, Lee JH, Fulp J, Thompson Z, Coppola D, Nicosia S, Sellers TA, McLaughlin J, Risch HA, Rosen B, Shaw P, Schildkraut J, Narod SA.

Br J Cancer. 2012 Nov 6;107(10):1783-90. doi: 10.1038/bjc.2012.452. Epub 2012 Oct 9.

PubMed [citation]

PMID:: 23047549
PMCID:: PMC3493867

In silico and in vivo splicing analysis of MLH1 and MSH2 missense mutations shows exon- and tissue-specific effects.

Lastella P, Surdo NC, Resta N, Guanti G, Stella A.

BMC Genomics. 2006 Sep 22;7:243.

PubMed [citation]

PMID:: 16995940
PMCID:: PMC1590028

See all PubMed Citations (9)

Details of each submission

From Counsyl, SCV000488060.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

#	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 Illumina Laboratory Services, Illumina, SCV001307795.1

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

Description

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown 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

From Baylor Genetics - CSER-TexasKidsCanSeq, SCV001482845.1

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

Description

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].

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

From Myriad Genetics, Inc., SCV004018165.1

#	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 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]. This variant has been observed in conjunction with multiple pathogenic variants, reducing the likelihood this variant itself is pathogenic.

#	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 St. Jude Molecular Pathology, St. Jude Children's Research Hospital, SCV004171497.1

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

Description

The MLH1 c.1166G>A (p.Arg389Gln) missense change has a maximum subpopulation frequency of 0.044% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL is inconclusive about a pathogenic or benign effect of this variant on protein function, and functional studies have shown mixed effects. One in vitro study demonstrated a similar mismatch repair activity compared to wildtype, while another showed a significantly reduced activity (PMID: 17510385 and 32849802, respectively). This variant has been reported in individuals with colorectal and ovarian cancer (PMID: 18383312, 23047549, 27121310, 28577310, 29069792, 34347074, 35263119). In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of 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: Sep 29, 2024

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