rs202038499

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 0P and 3B. BP4_ModerateBP6

The NM_000249.4(MLH1):​c.1379A>C​(p.Glu460Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000149 in 1,614,102 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000072 ( 0 hom., cov: 31)
Exomes 𝑓: 0.00016 ( 0 hom. )

Consequence

MLH1
NM_000249.4 missense

Scores

4
15

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:14

Conservation

PhyloP100: 3.31
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 -3 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.17076224).
BP6
Variant 3-37025977-A-C is Benign according to our data. Variant chr3-37025977-A-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 127613.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Benign=1, Likely_benign=10}. Variant chr3-37025977-A-C is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
MLH1NM_000249.4 linkc.1379A>C p.Glu460Ala 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.1379A>C p.Glu460Ala missense_variant Exon 12 of 19 1 NM_000249.4 ENSP00000231790.3 P40692-1

Frequencies

GnomAD3 genomes
AF:
0.0000723
AC:
11
AN:
152222
Hom.:
0
Cov.:
31
show subpopulations
Gnomad AFR
AF:
0.0000241
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000147
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000159
AC:
40
AN:
250798
Hom.:
0
AF XY:
0.000125
AC XY:
17
AN XY:
135758
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.0000462
Gnomad NFE exome
AF:
0.000344
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.000157
AC:
230
AN:
1461880
Hom.:
0
Cov.:
34
AF XY:
0.000153
AC XY:
111
AN XY:
727244
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.0000374
Gnomad4 NFE exome
AF:
0.000200
Gnomad4 OTH exome
AF:
0.0000993
GnomAD4 genome
AF:
0.0000723
AC:
11
AN:
152222
Hom.:
0
Cov.:
31
AF XY:
0.0000672
AC XY:
5
AN XY:
74360
show subpopulations
Gnomad4 AFR
AF:
0.0000241
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000147
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000100
Hom.:
0
Bravo
AF:
0.0000718
TwinsUK
AF:
0.000270
AC:
1
ALSPAC
AF:
0.000519
AC:
2
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000116
AC:
1
ExAC
AF:
0.000222
AC:
27
EpiCase
AF:
0.000164
EpiControl
AF:
0.000296

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:3Benign:14
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Uncertain:1Benign:4
-
Department of Pathology and Laboratory Medicine, Sinai Health System
Significance: Uncertain significance
Review Status: no assertion criteria provided
Collection Method: clinical testing

The MLH1 p.Glu460Ala variant was identified in 6 of 2074 proband chromosomes (frequency: 0.003) from individuals or families with Lynch syndrome, colorectal cancer, oligodendroglioma or glioblastoma and was not identified in 1440 control chromosomes from healthy individuals (Christensen 2008, Lagerstedt-Robinson 2016, Therkildsen 2015). The variant was also identified in dbSNP (ID: rs202038499) as "With other allele", ClinVar (classified as likely benign by Invitae, Ambry Genetics, GeneDx, and three other submitters; and as uncertain significance by two submitters), UMD-LSDB (1x unclassified variant), and in Insight Hereditary Tumors Database (8x). The variant was not identified in COGR, Cosmic, MutDB, Zhejiang University Database, or Mismatch Repair Genes Variant Database. The variant was identified in control databases in 39 of 277072 chromosomes at a frequency of 0.0001 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European in 38 of 126582 chromosomes (freq: 0.0003) and Finnish in 1 of 25794 chromosomes (freq: 0.00004), while the variant was not observed in the African, Ashkenazi Jewish, East Asian, Latino, Other, or South Asian populations. The p.Glu460 residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. The variant has been identified in patients with co-occurring pathogenic MSH2 variants (c.1277-?_1386+?del and p.Met663fs), increasing the likelihood that the p.Glu460Ala variant does not have clinical significance (Therkildsen 2015, Kansikas 2011, Christensen 2009) In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -

Jan 04, 2021
GeneDx
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25648859, 19697156, 23047549, 24933000, 18547406, 21120944, 27601186, 27146957, 26845104) -

-
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Dec 04, 2020
Quest Diagnostics Nichols Institute San Juan Capistrano
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

-
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

not specified Uncertain:1Benign:2
Oct 26, 2016
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Variant has been reported in 2 individuals with CRC who were both compound het for other MSH2 frameshift variants that segregated in the family. It is not present in ExAC. Variant classified in ClinVar as Likely Benign by Ambry, GeneDx, Invitae, and as VUS by U Wash (1 star). Variant is in a poorly conserved region. MaxMAF = 0.04% in ExAC (high for disease prevalence). -

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

- -

Nov 07, 2023
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Variant summary: MLH1 c.1379A>C (p.Glu460Ala) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00016 in 250798 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in MLH1 causing Lynch Syndrome (0.00016 vs 0.00071), allowing no conclusion about variant significance. c.1379A>C has been reported in the literature in individuals with cancer (Lagerstedt-Robinson_2016, Christensen_2008, Kansikas_2011, Delahunty_2022, Jarhelle_2019, Pal_2012, Therkildsen_2015, Svensson_2022, Jones_2015, Shirts_2016), however these report(s) do not provide unequivocal conclusions about association of the variant with Lynch Syndrome. Co-occurrences with other pathogenic variant(s) have been reported (MSH2, Exon 8 del; MSH2, p.M663fs), providing supporting evidence for a benign role (Kansikas_2011). At least one publication reports experimental evidence evaluating an impact on protein function. These results showed no effect on protein expression levels or repair efficiency (Christensen_2009). The following publications have been ascertained in the context of this evaluation (PMID: 25648859, 35263119, 21120944, 35430768, 25877891, 27601186, 26845104, 18547406, 31882575, 19697156, 23047549). 12 submitters have cited clinical-significance assessments for this variant to ClinVar after 2014; two submitters classified the variant as a variant of uncertain significance, while 10 submitters classified it as likely benign/benign. Based on the evidence outlined above, the variant was classified as likely benign. -

Colorectal cancer, hereditary nonpolyposis, type 2 Benign:3
Sep 01, 2021
Johns Hopkins Genomics, Johns Hopkins University
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Nov 27, 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]. -

Feb 15, 2017
Counsyl
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Benign:3
Oct 25, 2021
Sema4, Sema4
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: curation

- -

Nov 08, 2015
Color Diagnostics, LLC DBA Color Health
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Mar 05, 2019
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. -

Lynch syndrome Uncertain:1
Nov 20, 2015
University of Washington Department of Laboratory Medicine, University of Washington
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

MLH1-related disorder Benign:1
Sep 12, 2024
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 22, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.092
BayesDel_addAF
Benign
-0.051
T
BayesDel_noAF
Uncertain
0.0
CADD
Benign
16
DANN
Benign
0.97
DEOGEN2
Uncertain
0.42
T;.;.;.;.;.;T;T
Eigen
Benign
-0.78
Eigen_PC
Benign
-0.71
FATHMM_MKL
Benign
0.57
D
LIST_S2
Benign
0.62
T;T;.;.;.;T;D;D
M_CAP
Benign
0.063
D
MetaRNN
Benign
0.12
T;T;T;T;T;T;T;T
MetaSVM
Uncertain
-0.15
T
MutationAssessor
Benign
1.2
L;.;.;.;.;.;.;.
PrimateAI
Benign
0.35
T
PROVEAN
Benign
-1.5
N;N;N;N;N;N;D;N
REVEL
Uncertain
0.51
Sift
Benign
0.38
T;T;T;T;T;T;D;D
Sift4G
Benign
0.56
T;T;T;T;T;T;T;D
Polyphen
0.0
B;.;.;.;.;.;.;.
Vest4
0.80
MVP
0.97
MPC
0.070
ClinPred
0.043
T
GERP RS
3.2
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.048
gMVP
0.24

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: rs202038499; hg19: chr3-37067468; API