rs28756988

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001040108.2(MLH3):​c.2159A>G​(p.Tyr720Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00508 in 1,614,094 control chromosomes in the GnomAD database, including 386 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. Y720Y) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.027 ( 219 hom., cov: 33)
Exomes 𝑓: 0.0028 ( 167 hom. )

Consequence

MLH3
NM_001040108.2 missense

Scores

18

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13

Conservation

PhyloP100: 0.0840

Publications

7 publications found
Variant links:
Genes affected
MLH3 (HGNC:7128): (mutL homolog 3) This gene is a member of the MutL-homolog (MLH) family of DNA mismatch repair (MMR) genes. MLH genes are implicated in maintaining genomic integrity during DNA replication and after meiotic recombination. The protein encoded by this gene functions as a heterodimer with other family members. Somatic mutations in this gene frequently occur in tumors exhibiting microsatellite instability, and germline mutations have been linked to hereditary nonpolyposis colorectal cancer type 7 (HNPCC7). Several alternatively spliced transcript variants have been identified, but the full-length nature of only two transcript variants has been determined. [provided by RefSeq, Jul 2008]
MLH3 Gene-Disease associations (from GenCC):
  • colorectal cancer, hereditary nonpolyposis, type 7
    Inheritance: AD, AR Classification: MODERATE, LIMITED Submitted by: Ambry Genetics, ClinGen, Laboratory for Molecular Medicine

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.0017614067).
BP6
Variant 14-75047497-T-C is Benign according to our data. Variant chr14-75047497-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 314386.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BA1
GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0928 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
MLH3NM_001040108.2 linkc.2159A>G p.Tyr720Cys missense_variant Exon 2 of 13 ENST00000355774.7 NP_001035197.1 Q9UHC1-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
MLH3ENST00000355774.7 linkc.2159A>G p.Tyr720Cys missense_variant Exon 2 of 13 5 NM_001040108.2 ENSP00000348020.2 Q9UHC1-1
MLH3ENST00000380968.6 linkc.2159A>G p.Tyr720Cys missense_variant Exon 2 of 12 1 ENSP00000370355.3 Q9UHC1-2
MLH3ENST00000556257.5 linkc.2159A>G p.Tyr720Cys missense_variant Exon 2 of 7 5 ENSP00000451540.1 G3V419

Frequencies

GnomAD3 genomes
AF:
0.0273
AC:
4162
AN:
152188
Hom.:
219
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0954
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00975
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000828
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00633
Gnomad NFE
AF:
0.000206
Gnomad OTH
AF:
0.0191
GnomAD2 exomes
AF:
0.00711
AC:
1788
AN:
251336
AF XY:
0.00518
show subpopulations
Gnomad AFR exome
AF:
0.0992
Gnomad AMR exome
AF:
0.00382
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000141
Gnomad OTH exome
AF:
0.00310
GnomAD4 exome
AF:
0.00276
AC:
4038
AN:
1461788
Hom.:
167
Cov.:
35
AF XY:
0.00231
AC XY:
1681
AN XY:
727192
show subpopulations
African (AFR)
AF:
0.101
AC:
3393
AN:
33470
American (AMR)
AF:
0.00425
AC:
190
AN:
44724
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26132
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39684
South Asian (SAS)
AF:
0.000359
AC:
31
AN:
86256
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53378
Middle Eastern (MID)
AF:
0.00277
AC:
16
AN:
5768
European-Non Finnish (NFE)
AF:
0.0000746
AC:
83
AN:
1111984
Other (OTH)
AF:
0.00538
AC:
325
AN:
60392
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.487
Heterozygous variant carriers
0
248
496
743
991
1239
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Exome Hom
Variant carriers
0
110
220
330
440
550
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
AF:
0.0274
AC:
4166
AN:
152306
Hom.:
219
Cov.:
33
AF XY:
0.0260
AC XY:
1936
AN XY:
74478
show subpopulations
African (AFR)
AF:
0.0952
AC:
3957
AN:
41544
American (AMR)
AF:
0.00973
AC:
149
AN:
15308
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3468
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5194
South Asian (SAS)
AF:
0.000829
AC:
4
AN:
4828
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10622
Middle Eastern (MID)
AF:
0.00680
AC:
2
AN:
294
European-Non Finnish (NFE)
AF:
0.000206
AC:
14
AN:
68024
Other (OTH)
AF:
0.0189
AC:
40
AN:
2112
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.505
Heterozygous variant carriers
0
193
387
580
774
967
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Genome Hom
Variant carriers
0
42
84
126
168
210
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
Alfa
AF:
0.00992
Hom.:
158
Bravo
AF:
0.0318
ESP6500AA
AF:
0.0956
AC:
421
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.00880
AC:
1068
Asia WGS
AF:
0.00318
AC:
11
AN:
3476
EpiCase
AF:
0.000164
EpiControl
AF:
0.000296

ClinVar

Significance: Benign/Likely benign
Submissions summary: Benign:13
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:5
-
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)
Significance:Benign
Review Status:no assertion criteria provided
Collection Method:clinical testing

- -

-
Mayo Clinic Laboratories, Mayo Clinic
Significance:Benign
Review Status:no assertion criteria provided
Collection Method:clinical testing

- -

Jul 30, 2020
Ambry Genetics
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This alteration is classified as 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. -

Mar 04, 2025
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

-
Clinical Genetics, Academic Medical Center
Significance:Benign
Review Status:no assertion criteria provided
Collection Method:clinical testing

- -

Colorectal cancer, hereditary nonpolyposis, type 7 Benign:3
Apr 27, 2017
Illumina Laboratory Services, Illumina
Significance:Likely benign
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. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Jan 30, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Jul 07, 2023
KCCC/NGS Laboratory, Kuwait Cancer Control Center
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

not provided Benign:2
Jun 23, 2018
GeneDx
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

-
Breakthrough Genomics, Breakthrough Genomics
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:not provided

- -

Colorectal cancer;C0476089:Endometrial carcinoma;C1858380:Colorectal cancer, hereditary nonpolyposis, type 7 Benign:1
May 31, 2021
Department of Pathology and Laboratory Medicine, Sinai Health System
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

MLH3-related disorder Benign:1
Jun 12, 2019
PreventionGenetics, part of Exact Sciences
Significance:Benign
Review Status:no assertion criteria provided
Collection Method:clinical testing

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

Endometrial carcinoma Benign:1
Feb 01, 2025
KCCC/NGS Laboratory, Kuwait Cancer Control Center
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
0.059
BayesDel_addAF
Benign
-0.72
T
BayesDel_noAF
Benign
-0.73
CADD
Benign
1.6
DANN
Benign
0.28
DEOGEN2
Benign
0.070
T;.;.;T
Eigen
Benign
-1.4
Eigen_PC
Benign
-1.4
FATHMM_MKL
Benign
0.010
N
LIST_S2
Benign
0.68
T;T;T;.
MetaRNN
Benign
0.0018
T;T;T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
0.17
N;N;.;N
PhyloP100
0.084
PrimateAI
Benign
0.20
T
PROVEAN
Benign
0.32
N;.;N;N
REVEL
Benign
0.024
Sift
Benign
0.19
T;.;T;T
Sift4G
Benign
0.19
T;T;T;T
Polyphen
0.0
B;B;.;B
Vest4
0.053
MVP
0.22
MPC
0.13
ClinPred
0.0031
T
GERP RS
-2.7
Varity_R
0.037
gMVP
0.23
Mutation Taster
=299/1
polymorphism (auto)

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

Other links and lift over

dbSNP: rs28756988; hg19: chr14-75514200; COSMIC: COSV104587530; COSMIC: COSV104587530; API