rs63750361

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_000249.4(MLH1):​c.1166G>A​(p.Arg389Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000911 in 1,613,820 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00020 ( 0 hom., cov: 31)
Exomes 𝑓: 0.000079 ( 0 hom. )

Consequence

MLH1
NM_000249.4 missense

Scores

3
9
7

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:12B:7

Conservation

PhyloP100: 7.30
Variant links:
Genes affected
MLH1 (HGNC:7127): (mutL homolog 1) The protein encoded by this gene can heterodimerize with mismatch repair endonuclease PMS2 to form MutL alpha, part of the DNA mismatch repair system. When MutL alpha is bound by MutS beta and some accessory proteins, the PMS2 subunit of MutL alpha introduces a single-strand break near DNA mismatches, providing an entry point for exonuclease degradation. The encoded protein is also involved in DNA damage signaling and can heterodimerize with DNA mismatch repair protein MLH3 to form MutL gamma, which is involved in meiosis. This gene was identified as a locus frequently mutated in hereditary nonpolyposis colon cancer (HNPCC). [provided by RefSeq, Aug 2017]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.18663853).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
MLH1NM_000249.4 linkc.1166G>A p.Arg389Gln missense_variant Exon 12 of 19 ENST00000231790.8 NP_000240.1 P40692-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
MLH1ENST00000231790.8 linkc.1166G>A p.Arg389Gln missense_variant Exon 12 of 19 1 NM_000249.4 ENSP00000231790.3 P40692-1

Frequencies

GnomAD3 genomes
AF:
0.000211
AC:
32
AN:
151822
Hom.:
0
Cov.:
31
show subpopulations
Gnomad AFR
AF:
0.000533
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000131
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.000193
Gnomad SAS
AF:
0.000416
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000588
Gnomad OTH
AF:
0.000480
GnomAD3 exomes
AF:
0.0000557
AC:
14
AN:
251396
Hom.:
0
AF XY:
0.0000515
AC XY:
7
AN XY:
135856
show subpopulations
Gnomad AFR exome
AF:
0.000308
Gnomad AMR exome
AF:
0.0000289
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.000163
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000264
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000793
AC:
116
AN:
1461886
Hom.:
0
Cov.:
34
AF XY:
0.0000853
AC XY:
62
AN XY:
727246
show subpopulations
Gnomad4 AFR exome
AF:
0.000149
Gnomad4 AMR exome
AF:
0.0000224
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000756
Gnomad4 SAS exome
AF:
0.0000812
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000701
Gnomad4 OTH exome
AF:
0.000364
GnomAD4 genome
AF:
0.000204
AC:
31
AN:
151934
Hom.:
0
Cov.:
31
AF XY:
0.000189
AC XY:
14
AN XY:
74266
show subpopulations
Gnomad4 AFR
AF:
0.000531
Gnomad4 AMR
AF:
0.000131
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.000193
Gnomad4 SAS
AF:
0.000208
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000589
Gnomad4 OTH
AF:
0.000475
Alfa
AF:
0.000114
Hom.:
0
Bravo
AF:
0.000178
ESP6500AA
AF:
0.000681
AC:
3
ESP6500EA
AF:
0.000116
AC:
1
ExAC
AF:
0.0000741
AC:
9
Asia WGS
AF:
0.000866
AC:
3
AN:
3478
EpiCase
AF:
0.0000545
EpiControl
AF:
0.00

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:12Benign:7
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Colorectal cancer, hereditary nonpolyposis, type 2 Uncertain:4Benign:1
Nov 21, 2024
Myriad Genetics, Inc.
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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: 27363726]. This variant has been observed in conjunction with multiple pathogenic variants, reducing the likelihood this variant itself is pathogenic. -

Dec 18, 2015
Counsyl
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Feb 11, 2020
Baylor Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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

Oct 18, 2023
St. Jude Molecular Pathology, St. Jude Children's Research Hospital
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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. -

Jun 14, 2018
Illumina Laboratory Services, Illumina
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

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. -

not provided Uncertain:3Benign:2
Jun 24, 2022
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The MLH1 c.1166G>A; p.Arg389Gln variant (rs63750361) is reported in the literature in individuals with personal and/or a family history of colorectal cancer (Biscaglia 2022, Chang 2016, variant reported as p.R291Q), and is reported by multiple sources in ClinVar (Variation ID: 41633). One in vitro assay showed mismatch repair activity of 83.6% for the variant protein with >75% relative MLH1 expression (Takahashi 2007). However, another in vitro assay demonstrated mismatch repair activity of 13% for the variant protein compared to wildtype protein, and splicing assays show this variant may have an effect on splicing (Thompson 2020). This variant is found in the general population with an overall allele frequency of 0.007% (20/282620 alleles) in the Genome Aggregation Database. The arginine at codon 389 is moderately conserved, but computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.594). Based on available information, the clinical significance of this variant is uncertain at this time. References: Biscaglia G et al. Germline Alterations in Patients With IBD-associated Colorectal Cancer. Inflamm Bowel Dis. 2022 Mar 2;28(3):447-454. PMID: 34347074. Chang PY et al. NRAS germline variant G138R and multiple rare somatic mutations on APC in colorectal cancer patients in Taiwan by next generation sequencing. Oncotarget. 2016 Jun 21;7(25):37566-37580. PMID: 27121310. Takahashi M et al. Functional analysis of human MLH1 variants using yeast and in vitro mismatch repair assays. Cancer Res. 2007 May 15;67(10):4595-604. PMID: 17510385. Thompson BA et al. InSiGHT Variant Interpretation Committee. Contribution of mRNA Splicing to Mismatch Repair Gene Sequence Variant Interpretation. Front Genet. 2020 Jul 27;11:798. PMID: 32849802. -

May 19, 2021
GeneDx
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 26817999, 28873162, 16995940, 17510385, 22703879, 23047549, 18383312, 25579085, 25742471, 27300758, 26648449, 24933000, 27121310, 22290698, 32849802) -

Jul 13, 2012
Biesecker Lab/Clinical Genomics Section, National Institutes of Health
Significance: Uncertain significance
Review Status: no assertion criteria provided
Collection Method: research

- -

May 03, 2022
Revvity Omics, Revvity
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Aug 16, 2022
Quest Diagnostics Nichols Institute San Juan Capistrano
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

not specified Uncertain:4
Jun 07, 2024
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Variant summary: MLH1 c.1166G>A (p.Arg389Gln) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 5.9e-05 in 252668 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in MLH1 causing Hereditary Nonpolyposis Colorectal Cancer (5.9e-05 vs 0.00071), allowing no conclusion about variant significance. c.1166G>A has been reported in the literature in individuals affected with colorectal or ovarian cancer without strong evidence of causality (e.g. Chao_2008, Pal_2012, Chang_2016, Biscaglia_2022, Delahunty_2022). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Nonpolyposis Colorectal Cancer. Co-occurrence with another pathogenic variants has been reported (BRCA1 c.2241delC, p.Asp749fsX4, internal database), providing supporting evidence for a benign role. At least one publication reports experimental evidence evaluating an impact on protein function. These results showed no damaging effect of this variant (Takahashi_2007). The following publications have been ascertained in the context of this evaluation (PMID: 17510385, 18383312, 22703879, 23047549, 25579085, 26817999, 27121310, 14526391, 34347074, 35263119). ClinVar contains an entry for this variant (Variation ID: 41633). Based on the evidence outlined above, the variant was classified as VUS-possibly benign. -

Feb 20, 2017
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The p.Arg389Gln variant in MLH1 has been reported in 2 individuals with colorect al cancer (Chao 2008 and Chang 2016, variant reported as p.R291Q). It has also b een identified in 4/10400 of African chromosomes by the Exome Aggregation Consor tium (ExAC, http://exac.broadinstitute.org; dbSNP rs63750361). Please note that for diseases with clinical variability, reduced penetrance, or recessive inherit ance, pathogenic variants may be present at a low frequency in the general popul ation. Computational prediction tools and conservation analysis do not provide s trong support for or against an impact to the protein and in vitro testing did n ot demonstrate an impact on the mismatch repair (Takahashi 2007). In addition, this variant has been classified as a variant of uncertain significance on Septe mber 5, 2013 by the ClinGen approved InSIGHT expert panel (ClinVar SCV000106124. 2). In summary, the clinical significance of the p.Arg389Gln variant is uncertai n. -

Dec 03, 2014
Department of Pathology and Laboratory Medicine, Sinai Health System
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Mar 13, 2018
Genetic Services Laboratory, University of Chicago
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Benign:2
May 18, 2016
Color Diagnostics, LLC DBA Color Health
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Sep 10, 2018
Ambry Genetics
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Muir-Torré syndrome;C1333991:Colorectal cancer, hereditary nonpolyposis, type 2;C5399763:Mismatch repair cancer syndrome 1 Uncertain:1
Oct 31, 2018
Fulgent Genetics, Fulgent Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

MLH1-related disorder Benign:1
Dec 21, 2020
PreventionGenetics, part of Exact Sciences
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Hereditary nonpolyposis colorectal neoplasms Benign:1
Jan 23, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.11
BayesDel_addAF
Uncertain
0.023
T
BayesDel_noAF
Pathogenic
0.16
CADD
Pathogenic
26
DANN
Pathogenic
1.0
DEOGEN2
Uncertain
0.43
T;.;.;.;.;.
Eigen
Uncertain
0.48
Eigen_PC
Uncertain
0.56
FATHMM_MKL
Uncertain
0.96
D
LIST_S2
Pathogenic
0.99
D;D;.;.;.;D
M_CAP
Benign
0.084
D
MetaRNN
Benign
0.19
T;T;T;T;T;T
MetaSVM
Uncertain
0.44
D
MutationAssessor
Uncertain
2.4
M;.;.;.;.;.
PrimateAI
Uncertain
0.49
T
PROVEAN
Benign
-1.9
N;N;N;N;N;N
REVEL
Uncertain
0.59
Sift
Benign
0.13
T;T;D;D;D;T
Sift4G
Benign
0.28
T;T;T;T;T;T
Polyphen
0.60
P;.;.;.;.;.
Vest4
0.55
MVP
0.94
MPC
0.11
ClinPred
0.055
T
GERP RS
5.7
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.18
gMVP
0.34

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs63750361; hg19: chr3-37067255; COSMIC: COSV51618372; COSMIC: COSV51618372; API