rs63750361

Positions:

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

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]

MLH1 links:

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/exons	MANE	Protein	UniProt
MLH1	NM_000249.4 linkuse as main transcript	c.1166G>A	p.Arg389Gln	missense_variant	12/19	ENST00000231790.8	NP_000240.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MLH1	ENST00000231790.8 linkuse as main transcript	c.1166G>A	p.Arg389Gln	missense_variant	12/19	1	NM_000249.4	ENSP00000231790	P1	P40692-1

Frequencies

GnomAD3 genomes

AF:

0.000211

AC:

AN:

151822

Hom.:

Cov.:

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:

AN:

251396

Hom.:

AF XY:

0.0000515

AC XY:

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.:

Cov.:

AF XY:

0.0000853

AC XY:

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:

AN:

151934

Hom.:

Cov.:

AF XY:

0.000189

AC XY:

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.:

Bravo

AF:

0.000178

ESP6500AA

AF:

0.000681

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000741

AC:

Asia WGS

AF:

0.000866

AC:

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

Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Dec 18, 2015	- -
Uncertain significance, criteria provided, single submitter	clinical testing	St. Jude Molecular Pathology, St. Jude Children's Research Hospital	Oct 18, 2023	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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2018	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. -
Benign, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Mar 15, 2023	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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Feb 11, 2020	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

not provided

Uncertain:3Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Aug 16, 2022	- -
Uncertain significance, no assertion criteria provided	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jul 13, 2012	- -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jun 24, 2022	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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	May 03, 2022	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 19, 2021	This variant is associated with the following publications: (PMID: 26817999, 28873162, 16995940, 17510385, 22703879, 23047549, 18383312, 25579085, 25742471, 27300758, 26648449, 24933000, 27121310, 22290698, 32849802) -

not specified

Uncertain:4

Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 20, 2017	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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	Dec 03, 2014	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 07, 2024	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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Mar 13, 2018	- -

Hereditary cancer-predisposing syndrome

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	May 18, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Sep 10, 2018	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

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

MLH1-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 21, 2020

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

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Uncertain

0.023

BayesDel_noAF

Pathogenic

0.16

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.43

T;.;.;.;.;.

Eigen

Uncertain

0.48

Eigen_PC

Uncertain

0.56

FATHMM_MKL

Uncertain

0.96

LIST_S2

Pathogenic

0.99

D;D;.;.;.;D

M_CAP

Benign

0.084

MetaRNN

Benign

0.19

T;T;T;T;T;T

MetaSVM

Uncertain

0.44

MutationAssessor

Uncertain

2.4

M;.;.;.;.;.

MutationTaster

Benign

1.0

D;D;D;D;D;D

PrimateAI

Uncertain

0.49

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

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over